Jens Pahnke

• Gildenblat, Jacob; Stamnas, Jorunn & Pahnke, Jens (2026). Mass spectrometry imaging-based explainable machine learning reveals the biochemical landscapes of the mouse brain. Free Neuropathology. 7. doi: 10.17879/freeneuropathology-2026-9413. Fulltekst i vitenarkiv
• Sharma, Gaurav; Pahnke, Jens & Roth, Bernhard (2026). Polarimetric analysis of the Alzheimer’s pathology in excised mouse brain tissue. Journal of Biomedical Optics. ISSN 1083-3668. 31(1). doi: 10.1117/1.JBO.31.1.015002. Fulltekst i vitenarkiv
• Mairinger, Severin; Pfeiffer-Vogl, Jakob; Zachhuber, Lena; Stanek, Johann; Wanek, Thomas & Kuntner, Claudia [Vis alle 12 forfattere av denne artikkelen] (2026). Imaging pulmonary P-glycoprotein activity with aerosolized [99mTc]Tc-sestamibi in mice. European Journal of Pharmaceutical Sciences. ISSN 0928-0987. 221. doi: 10.1016/j.ejps.2026.107517. Fulltekst i vitenarkiv
• Gorska, Anna Maria; Sanz, Irene Santos Garcia; Kvasnička, Aleš; Dobešová, Dana; Friedecký, David & Gildenblat, Jacob [Vis alle 7 forfattere av denne artikkelen] (2026). ABCA7 deficiency exacerbates glutamate excitotoxicity in Alzheimer’s disease mice – A new pharmacological target for Glu-related neurotoxicity. Progress in Neurobiology. ISSN 0301-0082. 259. doi: 10.1016/j.pneurobio.2026.102891. Fulltekst i vitenarkiv Vis sammendrag

  Increasing attention has been directed towards the perturbation of glutamate (Glu) and γ-aminobutyric acid (GABA) homeostasis during the pathogenesis of Alzheimer's disease (AD). The prevailing disequilibrium, stemming from hyperactivation of the glutamatergic system, culminates in progressive neuronal impairment and cognitive deterioration. This study aimed to elucidate the contributory role of the ATP-binding cassette transporter A7 (ABCA7), identified as the second most critical genetic determinant in AD, in glutamatergic-associated neurotoxicity. This endeavor sought to advance molecular comprehension of neurological disorders where Glu-GABA neurotransmission represents a pivotal pharmacotherapeutic target. Utilizing multi-omics approaches, we rigorously analyzed four distinct mouse models, both with and without APPtg and ABCA7 expression, to simulate varied pathological and ABCA7-deficient states. Our results revealed amyloid-beta (Aβ) deposition as a catalyst for surging glutamatergic transmission. Notably, ABCA7 ablation exacerbated glutamatergic-induced neurotoxicity, attributed to diminished enzymatic activity related to neurotransmitter degradation and amplified expression levels of specific neurotransmitter transport proteins and receptor subunits, notably NMDA, AMPA, and GABAA. These findings furnish the first comprehensive description elucidating ABCA7's amplification of neurotoxic effects through modulation of Glu-GABA neurotransmission systems in neurodegenerative contexts, primarily mediated by lipid interaction. The evidence underscores ABCA7's imperative role in shaping future pharmacological strategies aimed at counteracting neurodegeneration precipitated by Glu-mediated neurotoxicity. This research advances the frontier for therapeutic exploration to ameliorate the deleterious neural consequences characteristic of neurodegenerative pathologies.

• Gildenblat, Jacob & Pahnke, Jens (2026). Dimensionality reduction with strong global structure preservation. Pattern Analysis and Applications. ISSN 1433-7541. 29(1). doi: 10.1007/s10044-025-01585-9. Fulltekst i vitenarkiv Vis sammendrag

  Modern dimensionality reduction (DR) methods, including t-SNE and UMAP, often distort global relationships, limiting the interpretability of embeddings. We introduce two complementary objectives that jointly preserve global geometry and local structure. Landmark Mantel Correlation (LMC) aligns high- and low-dimensional distances with respect to a small set of landmarks, providing an efficient global constraint. Multi-resolution Cluster Supervision (MiCS) promotes local fidelity by encouraging cluster assignments–estimated across multiple resolutions–to remain predictable after projection. Evaluated on 20 biomedical datasets, UMAP+LMC and MiCS+LMC achieve the best overall performance, demonstrating that global and local structure can be optimized simultaneously rather than being inherently conflicting. Our approach consistently outperforms existing methods for global and local structure preservation, yielding more reliable and interpretable visualizations.

• Gildenblat, Jacob & Pahnke, Jens (2025). Truthful visualizations for mass spectrometry imaging enable high spatial resolution interactive m/z mapping and exploration. bioRxiv - the preprint server for biology. doi: 10.1101/2025.03.18.643852. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Mass Spectrometry Imaging (MSI) provides complex molecular profiling pivotal for advanced biochemical analysis and diagnostics. We have identified an urgent need for computationally sophisticated, interactive, and automated visualization tools specifically designed for MSI analysis that employ dimensionality reduction (DR) methods to preserve global data structure. We present MSI-VISUAL, an open-source framework that enables rapid and intuitive MSI data exploration, providing panels of truthful visualizations and virtual pathology stains (VPS), with automatic and manual region selection, real-time verification, and statistical comparisons. Integrating established DR techniques, MSI-VISUAL introduces four novel visualization strategies: Saliency (SALO) and Spearman (SPEAR) Optimizations enhance global structure preservation across various distance metrics, addressing significant visualization challenges; TOP3 and Percentile Ratio (PR3D) provide memory-efficient and computationally rapid visualizations for large-scale datasets. In this work, comprehensive benchmarking and biological examples confirm that our DR visualizations surpass existing methods, facilitating the determination and quantification of subtle tissue differences at a single-cell level, revealing novel biological insights, and enabling diagnostic applications.

• Gildenblat, Jacob; Stamnæs, Jorunn & Pahnke, Jens (2025). Mass-spectrometry imaging-based explainable machine learning can be used to reveal biochemical landscapes of the brain. BioaRxiv. doi: 10.1101/2025.09.12.675752. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Recent computational advances in mass-spectrometry imaging (MSI) now enable unprecedented insight into organ-wide molecular composition and functional architecture. Here, we present a first example of a high-resolution, molecular-computational atlas of specific mouse brain lipids - acquired using a NEDC matrix and negative mode MSI - covering 123 anatomically defined regions with 191 polygonal annotations derived solely from the MSI data — no auxiliary imaging required. To overcome annotation ambiguity and MSI complexity, we introduced the Computational Brain Lipid Atlas (CBLA), a graph-based visual-explainability framework that generates virtual landscape visualizations (VLV) of specific lipids’ distributions across the brain substructures. The CBLA integrates dimensionality reduction and ensembles of supervised models to (i) refine annotations, (ii) elucidate interregional relationships, (iii) interpret model behavior, and (iv) formulate biologically testable hypotheses. The CBLA revealed novel lipid distribution patterns, functional integrations, anatomical connections - ’the brain’s telephone cables’, and region-specific disease signatures - disease networks in the basal ganglia. A new algorithm decomposes annotated regions into precise m/z features and resolves full-precision m/z values from MSI data, producing a comprehensive high-resolution brain map. It can be used for any MS measurements: metabolites, lipids, and peptides. This resource underpins downstream studies, exemplified here by characterizing the lipid molecular composition of A β plaques, their spatial arrangement, and their connections with the surrounding tissue. Highlights Mass Spectrometry Imaging (MSI) data were used to generate truthful visualizations for annotating brain regions with high resolution without the need for other modalities. MSI data were used to generate a computational atlas representation of the annotated brain regions. Pathological structures reveal their origin and their effects on specific brain networks. Anatomical regions and functional networks show specific lipid patterns. Brain stem nuclei and the white matter have a unique composition of lipids revealing their involvement in pathological networks. The atlas’ Virtual Landscape Visualizations (VLV) enable visualizing region-specific differences between different mouse models.

• Gildenblat, Jacob & Pahnke, Jens (2025). Dimensionality Reduction with Strong Global Structure Preservation. arXiv.org. ISSN 2331-8422. doi: 10.48550/arXiv.2503.07609. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Modern dimensionality reduction (DR) methods, including t-SNE and UMAP, often distort global relationships, limiting the interpretability of embeddings. We introduce two complementary objectives that jointly preserve global geometry and local structure. Landmark Mantel Correlation (LMC) aligns high- and low-dimensional distances with respect to a small set of landmarks, providing an efficient global constraint. Multi-resolution Cluster Supervision (MiCS) promotes local fidelity by encouraging cluster assignments—estimated across multiple resolutions—to remain predictable after projection. Evaluated on 20 biomedical datasets, UMAP+LMC and MiCS+LMC achieve the best overall performance, demonstrating that global and local structure can be optimized simultaneously rather than being inherently conflicting. Our approach consistently outperforms existing methods for global and local structure preservation, yielding more reliable and interpretable visualizations.

• Sagiv, Chen; Hadar, Ofir; Najjar, Abderrahman & Pahnke, Jens (2025). Artificial intelligence in surgical pathology – Where do we stand, where do we go? European Journal of Surgical Oncology. ISSN 0748-7983. 51(7), s. 1–8. doi: 10.1016/j.ejso.2024.109541. Fulltekst i vitenarkiv Vis sammendrag

  Surgical and neuropathologists continuously search for new and disease-specific features, such as independent predictors of tumor prognosis or determinants of tumor entities and sub-entities. This is a task where artificial intelligence (AI)/machine learning (ML) systems could significantly contribute to help with tumor outcome prediction and the search for new diagnostic or treatment stratification biomarkers. AI systems are increasingly integrated into routine pathology workflows to improve accuracy, reproducibility, productivity and to reveal difficult-to-see features in complicated histological slides, including the quantification of important markers for tumor grading and staging. In this article, we review the infrastructure needed to facilitate digital and computational pathology. We address the barriers for its full deployment in the clinical setting and describe the use of AI in intraoperative or postoperative settings were frozen or formalin-fixed, paraffin-embedded materials are used. We also summarize quality assessment issues of slide digitization, new spatial biology approaches, and the determination of specific gene-expression from whole slide images. Finally, we highlight new innovative and future technologies, such as large language models, optical biopsies, and mass spectrometry imaging.

• Wu, Jingyun; Sanz, Irene Santos Garcia; Delgado, Iván Eiriz; Brüning, Thomas; Kvasnička, Aleš & Friedecký, David [Vis alle 8 forfattere av denne artikkelen] (2025). Sex-dependent efficacy of sphingosine-1-phosphate receptor agonist FTY720 in mitigating Huntington's disease. Pharmacological Research. ISSN 1043-6618. 211. doi: 10.1016/j.phrs.2024.107557. Fulltekst i vitenarkiv Vis sammendrag

  Huntington's disease (HD) is a debilitating neurodegenerative disorder characterized by severe motor deficits, cognitive decline and psychiatric disturbances. An early and significant morphological hallmark of HD is the activation of astrocytes triggered by mutant huntingtin, leading to the release of inflammatory mediators. Fingolimod (FTY), an FDA-approved sphingosine-1-phosphate (S1P) receptor agonist is used to treat multiple sclerosis (MS), a neuroinflammatory disease, and has shown therapeutic promise in other neurological conditions. Our study aimed to investigate the therapeutic potential of FTY for treating HD by utilizing a well-characterized mouse model of HD (zQ175dn) and wild-type littermates. The study design included a crossover, long-term oral treatment with 1 mg/kg to 2 mg/kg FTY from the age of 15–46 weeks (n = 128). Different motor behavior and physiological parameters were assessed throughout the study. The findings revealed that FTY rescued disease-related body weight loss in a sex-dependent manner, indicating its potential to regulate metabolic disturbances and to counteract neurodegenerative processes in HD. FTY intervention also rescued testicular atrophy, restored testis tissue structure in male mice suggesting a broader impact on peripheral tissues affected by huntingtin pathology. Histological analyses of the brain revealed delayed accumulation of activated astrocytes contributing to the preservation of the neural microenvironment by reducing neuroinflammation. The extent of FTY-related disease improvement was sex-dependent. Motor functions and body weight improved mostly in female mice with sustained estrogen levels, whereas males had to compensate for the ongoing, disease-related testis atrophy and the loss of androgen production. Our study underscores the beneficial therapeutic effects of FTY on HD involving endogenous steroid hormones and their important anabolic effects. It positions FTY as a promising candidate for therapeutic interventions targeting various aspects of HD pathology. Further studies are needed to fully evaluate its therapeutic potential in patients.

• Sanz, Irene Santos Garcia; Bascuñana, Pablo; Brackhan, Mirjam; Villa-Cruz, Maria; Delgado, Iván Eiriz & Brüning, Thomas [Vis alle 7 forfattere av denne artikkelen] (2025). The ABC transporter A7 modulates neuroinflammation via NLRP3 inflammasome in Alzheimer’s disease mice. Alzheimer's Research & Therapy. 17(1). doi: 10.1186/s13195-025-01673-2. Fulltekst i vitenarkiv Vis sammendrag

  Background Specific genetic variants in the ATP-binding cassette transporter A7 locus (ABCA7) are associated with an increased risk of Alzheimer’s disease (AD). ABCA7 transports lipids from/across cell membranes, regulates Aβ peptide processing and clearance, and modulates microglial and T-cell functions to maintain immune homeostasis in the brain. During AD pathogenesis, neuroinflammation is one of the key mechanisms involved. Therefore, we wanted to investigate the specific role of ABCA7 in microglial activation via the NLRP3 inflammasome. Methods We developed the first humanized, Cre-inducible ABCA7flx knock-in mouse model, crossbred it with the APPPS1-21 β-amyloidosis model, and generated constitutive ABCA7ko and microglia Cx3cr1-specific conditional ABCA7ko AD mice. The role of ABCA7 was analyzed using histological, biochemical, molecular and mass spectrometry methods. Results Constitutive knockout of the Abca7 gene in APPPS1 mice increased the levels of Aβ42 and the number of IBA1+ (microglia) and GFAP+ (astrocytes) cells. Changes in the levels of astrocytes and microglia are associated with the activation of the NLRP3 inflammasome and increased levels of proinflammatory cytokines, such as IL1β and TNFα. Interestingly, microglia-specific ABCA7ko restored Aβ42 peptide levels and IBA1+ and GFAP+ and NLRP3-related gene expression to the original APPPS1 mouse levels. In primary glial cell cultures of APPPS1-hA7ko microglia and APPPS1 astrocytes from newborn pups, we observed that conditioned media from LPS-stimulated microglia was able to induce NLRP3 inflammasome expression and proinflammatory cytokine release in astrocytes. Conclusions Our data suggest that ABCA7 transporters regulate the communication between microglia and astrocytes through the NLRP3 inflammasome and the release of proinflammatory cytokines. This regulation implicates ABCA7 as a key driver ultimately involved in the persistence of the inflammatory response observed in AD.

• Mairinger, Severin; Jackwerth, Matthias; Chalampalakis, Zacharias; Rausch, Ivo; Weber, Maria & Wölfl-Duchek, Michael [Vis alle 13 forfattere av denne artikkelen] (2024). First-in-human evaluation of 6-bromo-7-[11C]methylpurine, a PET tracer for assessing the function of multidrug resistance-associated proteins in different tissues. European Journal of Nuclear Medicine and Molecular Imaging. ISSN 1619-7070. 51(13), s. 3900–3911. doi: 10.1007/s00259-024-06851-2. Fulltekst i vitenarkiv Vis sammendrag

  Purpose Multidrug resistance-associated protein 1 (MRP1) is a transport protein with a widespread tissue distribution, which has been implicated in the pathophysiology of Alzheimer’s and chronic respiratory disease. PET with 6-bromo-7-[11C]methylpurine ([11C]BMP) has been used to measure MRP1 function in rodents. In this study, [11C]BMP was for the first time characterised in humans to assess the function of MRP1 and other MRP subtypes in different tissues. Methods Thirteen healthy volunteers (7 men, 6 women) underwent dynamic whole-body PET scans on a long axial field-of-view (LAFOV) PET/CT system after intravenous injection of [11C]BMP. Three subjects of each sex were scanned a second time to assess reproducibility. Volumes of interest were outlined for MRP-expressing tissues (cerebral cortex, cerebellum, choroid plexus, retina, lungs, myocardium, kidneys, and liver). From the time-activity curves, the elimination rate constant (kE, h− 1) was derived as a parameter for tissue MRP function and its test-retest variability (TRTV, %) was calculated. Radiation dosimetry was calculated using the Medical Internal Radiation Dose (MIRD) methodology. Results Mean kE and corresponding TRTV values were: cerebral cortex: 0.055 ± 0.010 h− 1 (− 4 ± 24%), cerebellum: 0.033 ± 0.009 h− 1 (1 ± 39%), choroid plexus: 0.292 ± 0.059 h− 1 (0.1 ± 16%), retina: 0.234 ± 0.045 h− 1 (30 ± 38%), lungs: 0.875 ± 0.095 h− 1 (− 3 ± 11%), myocardium: 0.641 ± 0.105 h− 1 (11 ± 25%), kidneys: 1.378 ± 0.266 h− 1 (14 ± 16%), and liver: 0.685 ± 0.072 h− 1 (7 ± 9%). Significant sex differences were found for kE in the cerebellum, lungs and kidneys. Effective dose was 4.67 ± 0.18 µSv/MBq for men and 4.55 ± 0.18 µSv/MBq for women. Conclusion LAFOV PET/CT with [11C]BMP potentially allows for simultaneous assessment of MRP function in multiple human tissues. Mean TRTV of kE in different tissues was in an acceptable range, except for the retina. The radiation dosimetry of [11C]BMP was in the typical range of 11C-tracers. LAFOV PET/CT holds great potential to assess at a whole-body, multi-tissue level molecular targets relevant for drug disposition in humans.

• Gorska, Anna Maria; Sanz, Irene Santos Garcia; Eiriz, Iván; Brüning, Thomas; Nyman, Tuula Anneli & Pahnke, Jens (2024). Evaluation of cerebrospinal fluid (CSF) and interstitial fluid (ISF) mouse proteomes for the validation and description of Alzheimer's disease biomarkers. Journal of Neuroscience Methods. ISSN 0165-0270. 411:110239, s. 1–16. doi: 10.1016/j.jneumeth.2024.110239. Fulltekst i vitenarkiv Vis sammendrag

  Background Mass spectrometry (MS)-based cerebrospinal fluid (CSF) proteomics is an important method for discovering biomarkers of neurodegenerative diseases. CSF serves as a reservoir for interstitial fluid (ISF), and extensive communication between the two fluid compartments helps to remove waste products from the brain. New method We performed proteomic analyses of both CSF and ISF fluid compartments using intracerebral microdialysis to validate and detect novel biomarkers of Alzheimer's disease (AD) in APPtg and C57Bl/6J control mice. Results We identified up to 625 proteins in ISF and 4483 proteins in CSF samples. By comparing the biofluid profiles of APPtg and C57Bl/6J mice, we detected 37 and 108 significantly up- and downregulated candidates, respectively. In ISF, 7 highly regulated proteins, such as Gfap, Aldh1l1, Gstm1, and Txn, have already been implicated in AD progression, whereas in CSF, 9 out of 14 highly regulated proteins, such as Apba2, Syt12, Pgs1 and Vsnl1, have also been validated to be involved in AD pathogenesis. In addition, we also detected new interesting regulated proteins related to the control of synapses and neurotransmission (Kcna2, Cacng3, and Clcn6) whose roles as AD biomarkers should be further investigated. Comparison with existing methods This newly established combined protocol provides better insight into the mutual communication between ISF and CSF as an analysis of tissue or CSF compartments alone. Conclusions The use of multiple fluid compartments, ISF and CSF, for the detection of their biological communication enables better detection of new promising AD biomarkers.

• Menuawy, Ahmed El; Brüning, Thomas; Eiriz, Iván; Hähnel, Urs; Marthe, Frank & Möhle, Luisa [Vis alle 11 forfattere av denne artikkelen] (2024). Apolar Extracts of St. John’s Wort Alleviate the Effects of β-Amyloid Toxicity in Early Alzheimer’s Disease. International Journal of Molecular Sciences. ISSN 1661-6596. 25:1301(2), s. 1–16. doi: 10.3390/ijms25021301. Fulltekst i vitenarkiv Vis sammendrag

  Hypericum perforatum (St. John’s wort) has been described to be beneficial for the treatment of Alzheimer’s disease (AD). Different extractions have demonstrated efficiency in mice and humans, esp. extracts with a low hypericin and hyperforin content to reduce side effects such as phototoxicity. In order to systematically elucidate the therapeutic effects of H. perforatum extracts with different polarities, APP-transgenic mice were treated with a total ethanol extract (TE), a polar extract obtained from TE, and an apolar supercritical CO2 (scCO2) extract. The scCO2 extract was formulated with silicon dioxide (SiO2) for better oral application. APP-transgenic mice were treated with several extracts (total, polar, apolar) at different concentrations. We established an early treatment paradigm from the age of 40 days until the age of 80 days, starting before the onset of cerebral β-amyloid (Aβ) deposition at 45 days of age. Their effects on intracerebral soluble and insoluble Aβ were analyzed using biochemical analyses. Our study confirms that the scCO2 H. perforatum formulation shows better biological activity against Aβ-related pathological effects than the TE or polar extracts. Clinically, the treatment resulted in a dose-dependent improvement in food intake with augmentation of the body weight, and, biochemically, it resulted in a significant reduction in both soluble and insoluble Aβ (−27% and −25%, respectively). We therefore recommend apolar H. perforatum extracts for the early oral treatment of patients with mild cognitive impairment or early AD.

• Lauritzen, Trine; Munkhaugen, John; Bergan, Stein; Peersen, Kari; Svarstad, Anja Camilla & Andersen, Anders Mikal [Vis alle 9 forfattere av denne artikkelen] (2024). The atorvastatin metabolite pattern in muscle tissue and blood plasma is associated with statin muscle side effects in patients with coronary heart disease; An exploratory case-control study. Atherosclerosis Plus. ISSN 2667-0909. 55, s. 31–38. doi: 10.1016/j.athplu.2024.01.001. Fulltekst i vitenarkiv Vis sammendrag

  Background and aims Statin-associated muscle symptoms (SAMS) is a prevalent cause of statin discontinuation. It is challenging and time-consuming for clinicians to assess whether symptoms are caused by the statin or not, and diagnostic biomarkers are requested. Atorvastatin metabolites have been associated with SAMS. We aimed to compare atorvastatin pharmacokinetics between coronary heart disease (CHD) patients with and without clinically statin intolerance and statin-dependent histopathological alterations in muscle tissue. Secondarily we aimed to assess genetic variants relevant for the observed pharmacokinetic variables. Methods Twenty-eight patients with CHD and subjective SAMS were included in the exploratory MUSE biomarker study in 2020. Participants received atorvastatin 40 mg/day for seven weeks followed by no statins for eight weeks. Muscle biopsies and blood were collected at the end of each period. Four patients were categorized as clinically intolerant to ≥3 statins prior to study start whereas four patients had signs of muscle cell damage during treatment. Results We found significantly lower levels of atorvastatin acids, and higher lactone/acid ratios in the statin intolerant, both in muscle and plasma. With optimal cut-off, the combination of 2-OH-atorvastatin acid and the 2-OH-atorvastatin lactone/acid ratio provided sensitivity, specificity, and predictive values of 100 %. Patients with variants in UGT1A1 and UGT1A3 had higher lactone metabolite levels than those with wild type, both in muscle and plasma. Conclusion Atorvastatin metabolites appear promising as biomarkers for the identification of clinical statin intolerance in patients with self-perceive

• Jotanovic, Jelena; Boldt, Henning Bunsow; Burton, Mark; Andersen, Marianne; Bengtsson, Daniel & Bontell, Thomas Olsson [Vis alle 35 forfattere av denne artikkelen] (2024). Genome-wide methylation profiling differentiates benign from aggressive and metastatic pituitary neuroendocrine tumors. Acta Neuropathologica. ISSN 0001-6322. 148:68(1), s. 1–17. doi: 10.1007/s00401-024-02836-5. Fulltekst i vitenarkiv Vis sammendrag

  Aggressive pituitary neuroendocrine tumors (PitNETs)/adenomas are characterized by progressive growth despite surgery and all standard medical therapies and radiotherapy. A subset will metastasize to the brain and/or distant locations and are termed metastatic PitNETs (pituitary carcinomas). Studies of potential prognostic markers have been limited due to the rarity of these tumors. A few recurrent somatic mutations have been identified, and epigenetic alterations and chromosomal rearrangements have not been explored in larger cohorts of aggressive and metastatic PitNETs. In this study, we performed genome-wide methylation analysis, including copy-number variation (CNV) calculations, on tumor tissue specimens from a large international cohort of 64 patients with aggressive (48) and metastatic (16) pituitary tumors. Twelve patients with non-invasive pituitary tumors (Knosp 0–2) exhibiting an indolent course over a 5 year follow-up served as controls. In an unsupervised hierarchical cluster analysis, aggressive/metastatic PitNETs clustered separately from benign pituitary tumors, and, when only specimens from the first surgery were analyzed, three separate clusters were identified: aggressive, metastatic, and benign PitNETs. Numerous CNV events affecting chromosomal arms and whole chromosomes were frequent in aggressive and metastatic, whereas benign tumors had normal chromosomal copy numbers with only few alterations. Genome-wide methylation analysis revealed different CNV profiles and a clear separation between aggressive/metastatic and benign pituitary tumors, potentially providing biomarkers for identification of these tumors with a worse prognosis at the time of first surgery. The data may refine follow-up routines and contribute to the timely introduction of adjuvant therapy in patients harboring, or at risk of developing, aggressive or metastatic pituitary tumors.

• Rai, Surya Prakash; Krohn, Markus & Pahnke, Jens (2024). Early Cognitive Training Rescues Remote Spatial Memory but Reduces Cognitive Flexibility in Alzheimer's Disease Mice. I Raji, Cyrus A.; Leng, Yue; Ashford, J. Wesson & Khalsa, Dharma Singh (Red.), Ebook: Handbook of Intervention and Alzheimer’s Disease. IOS Press. ISSN 9781643685014. s. 55–76. doi: 10.3233/AIAD230073. Fulltekst i vitenarkiv
• Hernández-Lozano, Irene; Leterrier, Sarah; Mairinger, Severin; Stanek, Johann; Zacher, Anna S. & Breyer, Lara [Vis alle 12 forfattere av denne artikkelen] (2024). Performance and Sensitivity of [^99mTc]Tc-sestamibi Compared with Positron Emission Tomography Radiotracers to Measure P-glycoprotein Function in the Kidneys and Liver. Molecular Pharmaceutics. ISSN 1543-8384. 21(2), s. 932–943. doi: 10.1021/acs.molpharmaceut.3c01036. Fulltekst i vitenarkiv Vis sammendrag

  P-glycoprotein (P-gp, encoded in humans by the ABCB1 gene and in rodents by the Abcb1a/b genes) is a membrane transporter that can restrict the intestinal absorption and tissue distribution of many drugs and may also contribute to renal and hepatobiliary drug excretion. The aim of this study was to compare the performance and sensitivity of currently available radiolabeled P-gp substrates for positron emission tomography (PET) with the single-photon emission computed tomography (SPECT) radiotracer [99mTc]Tc-sestamibi for measuring the P-gp function in the kidneys and liver. Wild-type, heterozygous (Abcb1a/b(+/–)), and homozygous (Abcb1a/b(–/–)) Abcb1a/b knockout mice were used as models of different P-gp abundance in excretory organs. Animals underwent either dynamic PET scans after intravenous injection of [11C]N-desmethyl-loperamide, (R)-[11C]verapamil, or [11C]metoclopramide or consecutive static SPECT scans after intravenous injection of [99mTc]Tc-sestamibi. P-gp in the kidneys and liver of the mouse models was analyzed with immunofluorescence labeling and Western blotting. In the kidneys, Abcb1a/b() mice had intermediate P-gp abundance compared with wild-type and Abcb1a/b(−/−) mice. Among the four tested radiotracers, renal clearance of radioactivity (CLurine,kidney) was significantly reduced (−83%) in Abcb1a/b(–/–) mice only for [99mTc]Tc-sestamibi. Biliary clearance of radioactivity (CLbile,liver) was significantly reduced in Abcb1a/b(–/–) mice for [11C]N-desmethyl-loperamide (−47%), [11C]metoclopramide (−25%), and [99mTc]Tc-sestamibi (−79%). However, in Abcb1a/b(+/–) mice, CLbile,liver was significantly reduced (−47%) only for [99mTc]Tc-sestamibi. Among the tested radiotracers, [99mTc]Tc-sestamibi performed best in measuring the P-gp function in the kidneys and liver. Owing to its widespread clinical availability, [99mTc]Tc-sestamibi represents a promising probe substrate to assess systemic P-gp-mediated drug–drug interactions and to measure renal and hepatic P-gp function under different (patho-)physiological conditions.

• Villa-Cruz, Maria; Wu, Jingyun; Hansen, Stefanie M. & Pahnke, Jens (2024). Emerging Role of ABC Transporters in Glia Cells in Health and Diseases of the Central Nervous System. Cells. 13:740(9), s. 1–37. doi: 10.3390/cells13090740. Fulltekst i vitenarkiv
• Misiachna, Anna; Svobodova, Barbora; Netolicky, Jakub; Chvojkova, Marketa; Kleteckova, Lenka & Prchal, Lukas [Vis alle 24 forfattere av denne artikkelen] (2024). Phenoxytacrine derivatives: Low-toxicity neuroprotectants exerting affinity to ifenprodil-binding site and cholinesterase inhibition. European Journal of Medicinal Chemistry. ISSN 0223-5234. 266:116130, s. 1–23. doi: 10.1016/j.ejmech.2024.116130. Fulltekst i vitenarkiv Vis sammendrag

  Tacrine (THA), a long withdrawn drug, is still a popular scaffold used in medicinal chemistry, mainly for its good reactivity and multi-targeted effect. However, THA-associated hepatotoxicity is still an issue and must be considered in drug discovery based on the THA scaffold. Following our previously identified hit compound 7-phenoxytacrine (7-PhO-THA), we systematically explored the chemical space with 30 novel derivatives, with a focus on low hepatotoxicity, anticholinesterase action, and antagonism at the GluN1/GluN2B subtype of the NMDA receptor. Applying the down-selection process based on in vitro and in vivo pharmacokinetic data, two candidates, I-52 and II-52, selective GluN1/GluN2B inhibitors thanks to the interaction with the ifenprodil-binding site, have entered in vivo pharmacodynamic studies. Finally, compound I-52, showing only minor affinity to AChE, was identified as a lead candidate with favorable behavioral and neuroprotective effects using open-field and prepulse inhibition tests, along with scopolamine-based behavioral and NMDA-induced hippocampal lesion models. Our data show that compound I-52 exhibits low toxicity often associated with NMDA receptor ligands, and low hepatotoxicity, often related to THA-based compounds.

• Loiola, Rodrigo Azevedo; Nguyen, Cindy; Dib, Shiraz; Saint-Pol, Julien; Dehouck, Lucie & Sevin, Emmanuel [Vis alle 11 forfattere av denne artikkelen] (2024). 25-Hydroxycholesterol attenuates tumor necrosis factor alpha-induced blood-brain barrier breakdown in vitro. Biochimica et Biophysica Acta - Molecular Basis of Disease. ISSN 0925-4439. 1870:167479(8), s. 1–16. doi: 10.1016/j.bbadis.2024.167479. Fulltekst i vitenarkiv Vis sammendrag

  Intracellular cholesterol metabolism is regulated by the SREBP-2 and LXR signaling pathways. The effects of inflammation on these molecular mechanisms remain poorly studied, especially at the blood-brain barrier (BBB) level. Tumor necrosis factor α (TNFα) is a proinflammatory cytokine associated with BBB dysfunction. Therefore, the aim of our study was to investigate the effects of TNFα on BBB cholesterol metabolism, focusing on its underlying signaling pathways. Using a human in vitro BBB model composed of human brain-like endothelial cells (hBLECs) and brain pericytes (HBPs), we observed that TNFα increases BBB permeability by degrading the tight junction protein CLAUDIN-5 and activating stress signaling pathways in both cell types. TNFα also promotes cholesterol release and decreases cholesterol accumulation and APOE secretion. In hBLECs, the expression of SREBP-2 targets (LDLR and HMGCR) is increased, while ABCA1 expression is decreased. In HBPs, only LDLR and ABCA1 expression is increased. TNFα treatment also induces 25-hydroxycholesterol (25-HC) production, a cholesterol metabolite involved in the immune response and intracellular cholesterol metabolism. 25-HC pretreatment attenuates TNFα-induced BBB leakage and partially alleviates the effects of TNFα on ABCA1, LDLR, and HMGCR expression. Overall, our results suggest that TNFα favors cholesterol efflux via an LXR/ABCA1-independent mechanism at the BBB, while it activates the SREBP-2 pathway. Treatment with 25-HC partially reversed the effect of TNFα on the LXR/SREBP-2 pathways. Our study provides novel perspectives for better understanding cerebrovascular signaling events linked to BBB dysfunction and cholesterol metabolism in neuroinflammatory diseases.

• Mairinger, Severin; Jackwerth, Matthias; Soukup, Ondřej; Blaickner, Matthias; Decristoforo, Clemens & Nics, Lukas [Vis alle 10 forfattere av denne artikkelen] (2024). Advancing 6-bromo-7-[¹¹C]methylpurine to clinical use: improved regioselective radiosynthesis, non-clinical toxicity data and human dosimetry estimates. EJNMMI Radiopharmacy and Chemistry. 9:34(1), s. 1–13. doi: 10.1186/s41181-024-00265-z. Fulltekst i vitenarkiv Vis sammendrag

  Background 6-Bromo-7-[11C]methylpurine ([11C]BMP) is a radiotracer for positron emission tomography (PET) to measure multidrug resistance-associated protein 1 (MRP1) transport activity in different tissues. Previously reported radiosyntheses of [11C]BMP afforded a mixture of 7- and 9-[11C]methyl regioisomers. To prepare for clinical use, we here report an improved regioselective radiosynthesis of [11C]BMP, the results of a non-clinical toxicity study as well as human dosimetry estimates based on mouse PET data. Results [11C]BMP was synthesised by regioselective N7-methylation of 6-bromo-7H-purine (prepared under good manufacturing practice) with [11C]methyl triflate in presence of 2,2,6,6-tetramethylpiperidine magnesium chloride in a TRACERlab™ FX2 C synthesis module. [11C]BMP was obtained within a total synthesis time of approximately 43 min in a decay-corrected radiochemical yield of 20.5 ± 5.2%, based on starting [11C]methyl iodide, with a radiochemical purity > 99% and a molar activity at end of synthesis of 197 ± 130 GBq/μmol (n = 28). An extended single-dose toxicity study conducted in male and female Wistar rats under good laboratory practice after single intravenous (i.v.) administration of unlabelled BMP (2 mg/kg body weight) revealed no test item related adverse effects. Human dosimetry estimates, based on dynamic whole-body PET data in female C57BL/6J mice, suggested that an i.v. injected activity amount of 400 MBq of [11C]BMP will deliver an effective dose in the typical range of 11C-labelled radiotracers. Conclusions [11C]BMP can be produced in sufficient amounts and acceptable quality for clinical use. Data from the non-clinical safety evaluation showed no adverse effects and suggested that the administration of [11C]BMP will be safe and well tolerated in humans.

• Banca, Veronica La; Domenico, Sara De; Nicolai, Sara; Gatti, Veronica; Scalera, Stefano & Maugeri, Marcello [Vis alle 12 forfattere av denne artikkelen] (2024). ABCC1 Is a ΔNp63 Target Gene Overexpressed in Squamous Cell Carcinoma. International Journal of Molecular Sciences. ISSN 1661-6596. 25:8741(16), s. 1–14. doi: 10.3390/ijms25168741. Fulltekst i vitenarkiv Vis sammendrag

  The transcription factor ΔNp63 plays a pivotal role in maintaining the integrity of stratified epithelial tissues by regulating the expression of distinct target genes involved in lineage specification, cell stemness, cell proliferation and differentiation. Here, we identified the ABC transporter subfamily member ABCC1 as a novel ΔNp63 target gene. We found that in immortalized human keratinocytes and in squamous cell carcinoma (SCC) cells, ∆Np63 induces the expression of ABCC1 by physically occupying a p63-binding site (p63 BS) located in the first intron of the ABCC1 gene locus. In cutaneous SCC and during the activation of the keratinocyte differentiation program, ∆Np63 and ABCC1 levels are positively correlated raising the possibility that ABCC1 might be involved in the regulation of the proliferative/differentiative capabilities of squamous tissue. However, we did not find any gross alteration in the structure and morphology of the epidermis in humanized hABCC1 knock-out mice. Conversely, we found that the genetic ablation of ABCC1 led to a marked reduction in inflammation-mediated proliferation of keratinocytes, suggesting that ABCC1 might be involved in the regulation of keratinocyte proliferation upon inflammatory/proliferative signals. In line with these observations, we found a significant increase in ABCC1 expression in squamous cell carcinomas (SCCs), a tumor type characterized by keratinocyte hyper-proliferation and a pro-inflammatory tumor microenvironment. Collectively, these data uncover ABCC1 as an additional ∆Np63 target gene potentially involved in those skin diseases characterized by dysregulation of proliferation/differentiation balance.

• Stefan, Sven Marcel; Pahnke, Jens & Namasivayam, Vigneshwaran (2023). HD_BPMDS: a curated binary pattern multitarget dataset of Huntington’s disease–targeting agents. Journal of Cheminformatics. 15:109(1), s. 1–10. doi: 10.1186/s13321-023-00775-z. Fulltekst i vitenarkiv Vis sammendrag

  The discovery of both distinctive lead molecules and novel drug targets is a great challenge in drug discovery, which particularly accounts for orphan diseases. Huntington’s disease (HD) is an orphan, neurodegenerative disease of which the pathology is well-described. However, its pathophysiological background and molecular mechanisms are poorly understood. To date, only 2 drugs have been approved on the US and European markets, both of which address symptomatic aspects of this disease only. Although several hundreds of agents were described with efficacy against the HD phenotype in in vitro and/or in vivo models, a successful translation into clinical use is rarely achieved. Two major impediments are, first, the lack of awareness and understanding of the interactome—the sum of key proteins, cascades, and mediators—that contributes to HD initiation and progression; and second, the translation of the little gained knowledge into useful model systems. To counteract this lack of data awareness, we manually compiled and curated the entire modulator landscape of successfully evaluated pre-clinical small-molecule HD-targeting agents which are annotated with substructural molecular patterns, physicochemical properties, as well as drug targets, and which were linked to benchmark databases such as PubChem, ChEMBL, or UniProt. Particularly, the annotation with substructural molecular patterns expressed as binary code allowed for the generation of target-specific and -unspecific fingerprints which could be used to determine the (poly)pharmacological profile of molecular-structurally distinct molecules.

• Möhle, Luisa; Stefan, Katja; Almarcha, Pablo Bascuñana; Brackhan, Mirjam; Brüning, Thomas & Eiriz, Iván [Vis alle 14 forfattere av denne artikkelen] (2023). ABC Transporter C1 Prevents Dimethyl Fumarate from Targeting Alzheimer’s Disease. Biology (Basel). 12:932(7), s. 1–18. doi: 10.3390/biology12070932. Fulltekst i vitenarkiv Vis sammendrag

  Alzheimer’s disease (AD), the leading cause of dementia, is a growing health issue with very limited treatment options. To meet the need for novel therapeutics, existing drugs with additional preferred pharmacological profiles could be recruited. This strategy is known as ‘drug repurposing’. Here, we describe dimethyl fumarate (DMF), a drug approved to treat multiple sclerosis (MS), to be tested as a candidate for other brain diseases. We used an APP-transgenic model (APPtg) of senile β-amyloidosis mice to further investigate the potential of DMF as a novel AD therapeutic. We treated male and female APPtg mice through drinking water at late stages of β-amyloid (Aβ) deposition. We found that DMF treatment did not result in modulating effects on Aβ deposition at this stage. Interestingly, we found that glutathione-modified DMF interacts with the ATP-binding cassette transporter ABCC1, an important gatekeeper at the blood–brain and blood–plexus barriers and a key player for Aβ export from the brain. Our findings suggest that ABCC1 prevents the effects of DMF, which makes DMF unsuitable as a novel therapeutic drug against AD. The discovered effects of ABCC1 also have implications for DMF treatment of multiple sclerosis.

• Farfara, Dorit; Sooliman, Meital; Avrahami, Limor; Royal, Tabitha Grace; Amram, Shoshik & Rozenstein-Tsalkovich, Lea [Vis alle 12 forfattere av denne artikkelen] (2023). Physiological expression of mutated TAU impaired astrocyte activity and exacerbates β-amyloid pathology in 5xFAD mice. Journal of Neuroinflammation. 20:174(1), s. 1–15. doi: 10.1186/s12974-023-02823-9. Fulltekst i vitenarkiv Vis sammendrag

  Background Alzheimer’s disease (AD) is the leading cause of dementia in the world. The pathology of AD is affiliated with the elevation of both tau (τ) and β-amyloid (Aβ) pathologies. Yet, the direct link between natural τ expression on glia cell activity and Aβ remains unclear. While experiments in mouse models suggest that an increase in Aβ exacerbates τ pathology when expressed under a neuronal promoter, brain pathology from AD patients suggests an appearance of τ pathology in regions without Aβ. Methods Here, we aimed to assess the link between τ and Aβ using a new mouse model that was generated by crossing a mouse model that expresses two human mutations of the human MAPT under a mouse Tau natural promoter with 5xFAD mice that express human mutated APP and PS1 in neurons. Results The new mouse model, called 5xFAD TAU, shows accelerated cognitive impairment at 2 months of age, increased number of Aβ depositions at 4 months and neuritic plaques at 6 months of age. An expression of human mutated TAU in astrocytes leads to a dystrophic appearance and reduces their ability to engulf Aβ, which leads to an increased brain Aβ load. Astrocytes expressing mutated human TAU showed an impairment in the expression of vascular endothelial growth factor (VEGF) that has previously been suggested to play an important role in supporting neurons. Conclusions Our results suggest the role of τ in exacerbating Aβ pathology in addition to pointing out the potential role of astrocytes in disease progression. Further research of the crosstalk between τ and Aβ in astrocytes may increase our understanding of the role glia cells have in the pathology of AD with the aim of identifying novel therapeutic interventions to an otherwise currently incurable disease.

• Dib, Shiraz; Loiola, Rodrigo Azevedo; Sevin, Emmanuel; Saint-Pol, Julien; Shimizu, Fumitaka & Kanda, Takashi [Vis alle 8 forfattere av denne artikkelen] (2023). TNFα Activates the Liver X Receptor Signaling Pathway and Promotes Cholesterol Efflux from Human Brain Pericytes Independently of ABCA1. International Journal of Molecular Sciences. ISSN 1661-6596. 24:5992(6), s. 1–23. doi: 10.3390/ijms24065992. Fulltekst i vitenarkiv Vis sammendrag

  Neuroinflammation and brain lipid imbalances are observed in Alzheimer’s disease (AD). Tumor necrosis factor-α (TNFα) and the liver X receptor (LXR) signaling pathways are involved in both processes. However, limited information is currently available regarding their relationships in human brain pericytes (HBP) of the neurovascular unit. In cultivated HBP, TNFα activates the LXR pathway and increases the expression of one of its target genes, the transporter ATP-binding cassette family A member 1 (ABCA1), while ABCG1 is not expressed. Apolipoprotein E (APOE) synthesis and release are diminished. The cholesterol efflux is promoted, but is not inhibited, when ABCA1 or LXR are blocked. Moreover, as for TNFα, direct LXR activation by the agonist (T0901317) increases ABCA1 expression and the associated cholesterol efflux. However, this process is abolished when LXR/ABCA1 are both inhibited. Neither the other ABC transporters nor the SR-BI are involved in this TNFα-mediated lipid efflux regulation. We also report that inflammation increases ABCB1 expression and function. In conclusion, our data suggest that inflammation increases HBP protection against xenobiotics and triggers an LXR/ABCA1 independent cholesterol release. Understanding the molecular mechanisms regulating this efflux at the level of the neurovascular unit remains fundamental to the characterization of links between neuroinflammation, cholesterol and HBP function in neurodegenerative disorders.

• Mairinger, Severin; Leterrier, Sarah; Filip, Thomas; Löbsch, Mathilde; Pahnke, Jens & Hernández-Lozano, Irene [Vis alle 12 forfattere av denne artikkelen] (2023). [¹¹C]metoclopramide is a sensitive radiotracer to measure moderate decreases in P-glycoprotein function at the blood-brain barrier. Journal of Cerebral Blood Flow and Metabolism. ISSN 0271-678X. 44(1), s. 142–152. doi: 10.1177/0271678X231202336. Fulltekst i vitenarkiv
• Almarcha, Pablo Bascuñana; Brackhan, Mirjam; Möhle, Luisa; Wu, Jingyun; Brüning, Thomas & Delgado, Iván Eiriz [Vis alle 8 forfattere av denne artikkelen] (2023). Time- and Sex-Dependent Effects of Fingolimod Treatment in a Mouse Model of Alzheimer’s Disease. Biomolecules. 13: 331(2), s. 1–15. doi: 10.3390/biom13020331. Fulltekst i vitenarkiv Vis sammendrag

  Alzheimer’s disease (AD) is the most common cause of dementia. Fingolimod has previously shown beneficial effects in different animal models of AD. However, it has shown contradictory effects when it has been applied at early disease stages. Our objective was to evaluate fingolimod in two different treatment paradigms. To address this aim, we treated male and female APP-transgenic mice for 50 days, starting either before plaque deposition at 50 days of age (early) or at 125 days of age (late). To evaluate the effects, we investigated the neuroinflammatory and glial markers, the Aβ load, and the concentration of the brain-derived neurotrophic factor (BDNF). We found a reduced Aβ load only in male animals in the late treatment paradigm. These animals also showed reduced microglia activation and reduced IL-1β. No other treatment group showed any difference in comparison to the controls. On the other hand, we detected a linear correlation between BDNF and the brain Aβ concentrations. The fingolimod treatment has shown beneficial effects in AD models, but the outcome depends on the neuroinflammatory state at the start of the treatment. Thus, according to our data, a fingolimod treatment would be effective after the onset of the first AD symptoms, mainly affecting the neuroinflammatory reaction to the ongoing Aβ deposition.

• Kolnes, Anders Jensen; Øystese, Kristin Astrid Berland; Sjöstedt, Evelina; Olarescu, Nicoleta Cristina; Heck, Ansgar & Pahnke, Jens [Vis alle 12 forfattere av denne artikkelen] (2023). TGFBR3L is associated with gonadotropin production in non-functioning gonadotroph pituitary neuroendocrine tumours. Pituitary. ISSN 1386-341X. 26, s. 227–236. doi: 10.1007/s11102-023-01310-x. Fulltekst i vitenarkiv Vis sammendrag

  Purpose Transforming growth factor-beta receptor 3-like (TGFBR3L) is a pituitary enriched membrane protein selectively detected in gonadotroph cells. TGFBR3L is named after transforming growth factor-beta receptor 3 (TGFBR3), an inhibin A co-receptor in mice, due to sequence identity to the C-terminal region. We aimed to characterize TGFBR3L detection in a well-characterized, prospectively collected cohort of non-functioning pituitary neuroendocrine tumours (NF-PitNETs) and correlate it to clinical data. Methods 144 patients operated for clinically NF-PitNETs were included. Clinical, radiological and biochemical data were recorded. Immunohistochemical (IHC) staining for FSHβ and LHβ was scored using the immunoreactive score (IRS), TGFBR3L and TGFBR3 were scored by the percentage of positive stained cells. Results TGFBR3L staining was selectively present in 52% of gonadotroph tumours. TGFBR3L was associated to IRS of LHβ (median 2 [IQR 0–3] in TGFBR3L negative and median 6 [IQR 3–9] in TGFBR3L positive tumours, p < 0.001), but not to the IRS of FSHβ (p = 0.32). The presence of TGFBR3L was negatively associated with plasma gonadotropin concentrations in males (P-FSH median 5.5 IU/L [IQR 2.9–9.6] and median 3.0 [IQR 1.8–5.6] in TGFBR3L negative and positive tumours respectively, p = 0.008) and P-LH (median 2.8 IU/L [IQR 1.9–3.7] and median 1.8 [IQR 1.1-3.0] in TGFBR3L negative and positive tumours respectively, p = 0.03). TGFBR3 stained positive in 22% (n = 25) of gonadotroph tumours with no correlation to TGFBR3L. Conclusion TGFBR3L was selectively detected in half (52%) of gonadotroph NF-PitNETs. The association to LHβ staining and plasma gonadotropins suggests that TGFBR3L may be involved in hormone production in gonadotroph NF-PitNETs.

• Wölfl‐Duchek, Michael; Mairinger, Severin; Hernández-Lozano, Irene; Filip, Thomas; Zoufal, Viktoria & Löbsch, Mathilde [Vis alle 12 forfattere av denne artikkelen] (2022). Use of PET Imaging to Assess the Efficacy of Thiethylperazine to Stimulate Cerebral MRP1 Transport Activity in Wild‐Type and APP/PS1‐21 Mice. International Journal of Molecular Sciences. ISSN 1661-6596. 23:6514(12), s. 1–12. doi: 10.3390/ijms23126514. Fulltekst i vitenarkiv Vis sammendrag

  Multidrug resistance-associated protein 1 (MRP1, encoded by the ABCC1 gene) may contribute to the clearance of amyloid-beta (Aβ) peptides from the brain into the blood and stimulation of MRP1 transport activity may be a therapeutic approach to enhance brain Aβ clearance. In this study, we assessed the effect of thiethylperazine, an antiemetic drug which was shown to stimulate MRP1 activity in vitro and to decrease Aβ load in a rapid β-amyloidosis mouse model (APP/PS1-21), on MRP1 transport activity by means of positron emission tomography (PET) imaging with the MRP1 tracer 6-bromo-7-[11C]methylpurine. Groups of wild-type, APP/PS1-21 and Abcc1(−/−) mice underwent PET scans before and after a 5-day oral treatment period with thiethylperazine (15 mg/kg, once daily). The elimination rate constant of radioactivity (kelim) was calculated from time–activity curves in the brain and the lungs as a measure of tissue MRP1 activity. Treatment with thiethylperazine had no significant effect on MRP1 activity in the brain and the lungs of wild-type and APP/PS1-21 mice. This may either be related to a lack of an MRP1-stimulating effect of thiethylperazine in vivo or to other factors, such as substrate-dependent MRP1 stimulation, insufficient target tissue exposure to thiethylperazine or limited sensitivity of the PET tracer to measure MRP1 stimulation.

• Puri, Sachin; Stefan, Katja; Khan, Sharuk L.; Pahnke, Jens; Stefan, Sven Marcel & Juvale, Kapil (2022). Indole Derivatives as New Structural Class of Potent and Antiproliferative Inhibitors of Monocarboxylate Transporter 1 (MCT1; SLC16A1). Journal of Medicinal Chemistry. ISSN 0022-2623. 66(1), s. 657–676. doi: 10.1021/acs.jmedchem.2c01612. Fulltekst i vitenarkiv Vis sammendrag

  The solute carrier (SLC) monocarboxylate transporter 1 (MCT1; SLC16A1) represents a promising target for the treatment of cancer; however, the MCT1 modulator landscape is underexplored with only roughly 100 reported compounds. To expand the knowledge about MCT1 modulation, we synthesized a library of 16 indole-based molecules and subjected these to a comprehensive biological assessment platform. All compounds showed functional inhibitory activities against MCT1 at low nanomolar concentrations and great antiproliferative activities against the MCT1-expressing cancer cell lines A-549 and MCF-7, while the compounds were selective over MCT4 (SLC16A4). Lead compound 24 demonstrated a greater potency than the reference compound, and molecular docking revealed strong binding affinities to MCT1. Compound 24 led to cancer cell cycle arrest as well as apoptosis, and it showed to sensitize these cancer cells toward an antineoplastic agent. Strikingly, compound 24 had also significant inhibitory power against the multidrug transporter ABCB1 and showed to reverse ABCB1-mediated multidrug resistance (MDR).

• Namasivayam, Vigneshwaran; Stefan, Katja; Gorecki, Lukas; Korabecny, Jan; Soukup, Ondrej & Jansson, Patric Jan [Vis alle 8 forfattere av denne artikkelen] (2022). Physicochemistry shapes bioactivity landscape of pan-ABC transporter modulators: Anchor point for innovative Alzheimer's disease therapeutics. International Journal of Biological Macromolecules. ISSN 0141-8130. 217, s. 775–791. doi: 10.1016/j.ijbiomac.2022.07.062. Fulltekst i vitenarkiv Vis sammendrag

  Alzheimer‘s disease (AD) is a devastating neurological disorder characterized by the pathological accumulation of macromolecular Aβ and tau leading to neuronal death. Drugs approved to treat AD may ameliorate disease symptoms, however, no curative treatment exists. Aβ peptides were discovered to be substrates of adenosine triphosphate-(ATP)-binding cassette (ABC) transporters. Activators of these membrane-bound efflux proteins that promote binding and/or translocation of Aβ could revolutionize AD medicine. The knowledge about ABC transporter activators is very scarce, however, the few molecules that were reported contain substructural features of multitarget (pan-)ABC transporter inhibitors. A cutting-edge strategy to obtain new drug candidates is to explore and potentially exploit the recently proposed multitarget binding site of pan-ABC transporter inhibitors as anchor point for the development of innovative activators to promote Aβ clearance from the brain. Molecular associations between functional bioactivities and physicochemical properties of small-molecules are key to understand these processes. This study provides an analysis of a recently reported unique multitarget dataset for the correlation between multitarget bioactivity and physicochemistry. Six novel pan-ABC transporter inhibitors were validated containing substructural features of ABC transporter activators, which underpins the relevance of the multitarget binding site for the targeted development of novel AD diagnostics and therapeutics.

• Namasivayam, Vigneshwaran; Stefan, Katja; Silbermann, Katja; Pahnke, Jens; Wiese, Michael & Stefan, Sven Marcel (2022). Structural feature-driven pattern analysis for multitarget modulator landscapes. Bioinformatics. ISSN 1367-4803. 38(5), s. 1385–1392. doi: 10.1093/bioinformatics/btab832. Fulltekst i vitenarkiv Vis sammendrag

  Motivation Multitargeting features of small molecules have been of increasing interest in recent years. Polypharmacological drugs that address several therapeutic targets may provide greater therapeutic benefits for patients. Furthermore, multitarget compounds can be used to address proteins of the same (or similar) protein families for their exploration as potential pharmacological targets. In addition, the knowledge of multitargeting features is of major importance in the drug selection process; particularly in ultra-large virtual screening procedures to gain high-quality compound collections. However, large-scale multitarget modulator landscapes are almost non-existent. Results We implemented a specific feature-driven computer-aided pattern analysis (C@PA) to extract molecular-structural features of inhibitors of the model protein family of ATP-binding cassette (ABC) transporters. New molecular-structural features have been identified that successfully expanded the known multitarget modulator landscape of pan-ABC transporter inhibitors. The prediction capability was biologically confirmed by the successful discovery of pan-ABC transporter inhibitors with a distinct inhibitory activity profile.

• Stefan, Sven Marcel; Jansson, Patric Jan; Pahnke, Jens & Namasivayam, Vigneshwaran (2022). A curated binary pattern multitarget dataset of focused ATP-binding cassette transporter inhibitors. Scientific Data. 9:446(1), s. 1–14. doi: 10.1038/s41597-022-01506-z. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Multitarget datasets that correlate bioactivity landscapes of small-molecules toward different related or unrelated pharmacological targets are crucial for novel drug design and discovery. ATP-binding cassette (ABC) transporters are critical membrane-bound transport proteins that impact drug and metabolite distribution in human disease as well as disease diagnosis and therapy. Molecular-structural patterns are of the highest importance for the drug discovery process as demonstrated by the novel drug discovery tool ‘computer-aided pattern analysis’ (‘C@PA’). Here, we report a multitarget dataset of 1,167 ABC transporter inhibitors analyzed for 604 molecular substructures in a statistical binary pattern distribution scheme. This binary pattern multitarget dataset (ABC_BPMDS) can be utilized for various areas. These areas include the intended design of (i) polypharmacological agents, (ii) highly potent and selective ABC transporter-targeting agents, but also (iii) agents that avoid clearance by the focused ABC transporters [ e.g ., at the blood-brain barrier (BBB)]. The information provided will not only facilitate novel drug prediction and discovery of ABC transporter-targeting agents, but also drug design in general in terms of pharmacokinetics and pharmacodynamics.

• Brackhan, Mirjam; Calza, Giulio; Lundgren, Kristiina; Bascuñana, Pablo; Brüning, Thomas & Soliymani, Rabah [Vis alle 11 forfattere av denne artikkelen] (2022). Isotope-labeled amyloid-β does not transmit to the brain in a prion-like manner after peripheral administration. EMBO Reports. ISSN 1469-221X. 23:e54405(7), s. 1–15. doi: 10.15252/embr.202154405. Fulltekst i vitenarkiv Vis sammendrag

  Findings of early cerebral amyloid-β deposition in mice after peripheral injection of amyloid-β-containing brain extracts, and in humans following cadaveric human growth hormone treatment raised concerns that amyloid-β aggregates and possibly Alzheimer’s disease may be transmissible between individuals. Yet, proof that Aβ actually reaches the brain from the peripheral injection site is lacking. Here, we use a proteomic approach combining stable isotope labeling of mammals and targeted mass spectrometry. Specifically, we generate 13C-isotope-labeled brain extracts from mice expressing human amyloid-β and track 13C-lysine-labeled amyloid-β after intraperitoneal administration into young amyloid precursor protein-transgenic mice. We detect injected amyloid-β in the liver and lymphoid tissues for up to 100 days. In contrast, injected 13C-lysine-labeled amyloid-β is not detectable in the brain whereas the mice incorporate 13C-lysine from the donor brain extracts into endogenous amyloid-β. Using a highly sensitive and specific proteomic approach, we demonstrate that amyloid-β does not reach the brain from the periphery. Our study argues against potential transmissibility of Alzheimer’s disease while opening new avenues to uncover mechanisms of pathophysiological protein deposition.

• Wu, Jingyun; Möhle, Luisa; Brüning, Thomas; Delgado, Iván Eiriz; Rafehi, Muhammad & Stefan, Katja [Vis alle 8 forfattere av denne artikkelen] (2022). A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development. International Journal of Molecular Sciences. ISSN 1661-6596. 23:14763(23), s. 1–36. doi: 10.3390/ijms232314763. Fulltekst i vitenarkiv Vis sammendrag

  Huntington’s disease (HD) is a lethal neurodegenerative disorder without efficient therapeutic options. The inefficient translation from preclinical and clinical research into clinical use is mainly attributed to the lack of (i) understanding of disease initiation, progression, and involved molecular mechanisms; (ii) knowledge of the possible HD target space and general data awareness; (iii) detailed characterizations of available disease models; (iv) better suitable models; and (v) reliable and sensitive biomarkers. To generate robust HD-like symptoms in a mouse model, the neomycin resistance cassette was excised from zQ175 mice, generating a new line: zQ175Δneo. We entirely describe the dynamics of behavioral, neuropathological, and immunohistological changes from 15–57 weeks of age. Specifically, zQ175Δneo mice showed early astrogliosis from 15 weeks; growth retardation, body weight loss, and anxiety-like behaviors from 29 weeks; motor deficits and reduced muscular strength from 36 weeks; and finally slight microgliosis at 57 weeks of age. Additionally, we collected the entire bioactivity network of small-molecule HD modulators in a multitarget dataset (HD_MDS). Hereby, we uncovered 358 unique compounds addressing over 80 different pharmacological targets and pathways. Our data will support future drug discovery approaches and may serve as useful assessment platform for drug discovery and development against HD.

• Hegrand, Myra Østrem & Pahnke, Jens (2021). Godkjenning først, forskning etterpå? Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 141(13), s. 1–3. doi: 10.4045/tidsskr.21.0590. Fulltekst i vitenarkiv
• Tranulis, Michael A.; Grahek-Ogden, Danica; Kapperud, Georg; Pahnke, Jens; Aspholm, Marina Elisabeth & Jore, Solveig [Vis alle 11 forfattere av denne artikkelen] (2021). Oppdatert kunnskap om det zoonotiske potensialet av skrantesjuke ved håndtering av slakt og konsum av kjøtt. Vitenskapelig uttalelse fra faggruppen for hygiene og smittestoffer i Vitenskapskomiteen for mat og miljø. VKM Report. 2021(8). Fulltekst i vitenarkiv
• Namasivayam, Vigneshwaran; Stefan, Katja; Pahnke, Jens & Stefan, Sven Marcel (2021). Binding mode analysis of ABCA7 for the prediction of novel Alzheimer's disease therapeutics. Computational and Structural Biotechnology Journal. 19, s. 6490–6504. doi: 10.1016/j.csbj.2021.11.035. Fulltekst i vitenarkiv Vis sammendrag

  The adenosine-triphosphate-(ATP)-binding cassette (ABC) transporter ABCA7 is a genetic risk factor for Alzheimer’s disease (AD). Defective ABCA7 promotes AD development and/or progression. Unfortunately, ABCA7 belongs to the group of ‘under-studied’ ABC transporters that cannot be addressed by small-molecules. However, such small-molecules would allow for the exploration of ABCA7 as pharmacological target for the development of new AD diagnostics and therapeutics. Pan-ABC transporter modulators inherit the potential to explore under-studied ABC transporters as novel pharmacological targets by potentially binding to the proposed ‘multitarget binding site’. Using the recently reported cryogenic-electron microscopy (cryo-EM) structures of ABCA1 and ABCA4, a homology model of ABCA7 has been generated. A set of novel, diverse, and potent pan-ABC transporter inhibitors has been docked to this ABCA7 homology model for the discovery of the multitarget binding site. Subsequently, application of pharmacophore modelling identified the essential pharmacophore features of these compounds that may support the rational drug design of innovative diagnostics and therapeutics against AD.

• Pahnke, Jens; Almarcha, Pablo Bascuñana; Brackhan, Mirjam; Stefan, Katja; Namasivayam, Vigneshwaran & Koldamova, Radosveta [Vis alle 9 forfattere av denne artikkelen] (2021). Strategies to gain novel Alzheimer’s disease diagnostics and therapeutics using modulators of ABCA transporters. Free Neuropathology. 2, s. 1–69. doi: 10.17879/freeneuropathology-2021-3528. Fulltekst i vitenarkiv Vis sammendrag

  Adenosine-triphosphate-(ATP)-binding cassette (ABC) transport proteins are ubiquitously present membrane-bound efflux pumps that distribute endo- and xenobiotics across intra- and intercellular barriers. Discovered over 40 years ago, ABC transporters have been identified as key players in various human diseases, such as multidrug-resistant cancer and atherosclerosis, but also neurodegenerative diseases, such as Alzheimer’s disease (AD). Most prominent and well-studied are ABCB1, ABCC1, and ABCG2, not only due to their contribution to the multidrug resistance (MDR) phenotype in cancer, but also due to their contribution to AD. However, our understanding of other ABC transporters is limited, and most of the 49 human ABC transporters have been largely neglected as potential targets for novel small-molecule drugs. This is especially true for the ABCA subfamily, which contains several members known to play a role in AD initiation and progression. This review provides up-to-date information on the proposed functional background and pathological role of ABCA transporters in AD. We also provide an overview of small-molecules shown to interact with ABCA transporters as well as potential in silico, in vitro, and in vivo methodologies to gain novel templates for the development of innovative ABC transporter-targeting diagnostics and therapeutics.

• Upite, Jolanta; Brüning, Thomas; Möhle, Luisa; Brackhan, Mirjam; Almarcha, Pablo Bascuñana & Jansone, Baiba [Vis alle 7 forfattere av denne artikkelen] (2021). A New Tool for the Analysis of the Effect of Intracerebrally Injected Anti-Amyloid-β Compounds. Journal of Alzheimer's Disease. ISSN 1387-2877. 84(4), s. 1677–1690. doi: 10.3233/JAD-215180. Fulltekst i vitenarkiv Vis sammendrag

  Background: A wide range of techniques has been developed over the past decades to characterize amyloid-β (Aβ) pathology in mice. Until now, no method has been established to quantify spatial changes in Aβ plaque deposition due to targeted delivery of substances using ALZET® pumps. Objective: Development of a methodology to quantify the local distribution of Aβ plaques after intracerebral infusion of compounds. Methods: We have developed a toolbox to quantify Aβ plaques in relation to intracerebral injection channels using Zeiss AxioVision® and Microsoft Excel® software. For the proof of concept, intracerebral stereotactic surgery was performed in 50-day-old APP-transgenic mice injected with PBS. At the age of 100 days, brains were collected for immunhistological analysis. Results: The toolbox can be used to analyze and evaluate Aβ plaques (number, size, and coverage) in specific brain areas based on their location relative to the point of the injection or the injection channel. The tool provides classification of Aβ plaques in pre-defined distance groups using two different approaches. Conclusion: This new analytic toolbox facilitates the analysis of long-term continuous intracerebral experimental compound infusions using ALZET® pumps. This method generates reliable data for Aβ deposition characterization in relation to the distribution of experimental compounds.

• Bascuñana, Pablo; Brackhan, Mirjam & Pahnke, Jens (2021). Machine Learning-Supported Analyses Improve Quantitative Histological Assessments of Amyloid-β Deposits and Activated Microglia. Journal of Alzheimer's Disease. ISSN 1387-2877. 79(2), s. 597–605. doi: 10.3233/JAD-201120. Fulltekst i vitenarkiv Vis sammendrag

  Background: Detailed pathology analysis and morphological quantification is tedious and prone to errors. Automatic image analysis can help to increase objectivity and reduce time. Here, we present the evaluation of the DeePathology STUDIO™ for automatic analysis of histological whole-slide images using machine learning/artificial intelligence. Objective: To evaluate and validate the use of DeePathology STUDIO for the analysis of histological slides at high resolution. Methods: We compared the DeePathology STUDIO and our current standard method using macros in AxioVision for the analysis of amyloid-β (Aβ) plaques and microglia in APP-transgenic mice at different ages. We analyzed density variables and total time invested with each approach. In addition, we correlated Aβ concentration in brain tissue measured by ELISA with the results of Aβ staining analysis. Results: DeePathology STUDIO showed a significant decrease of the time for establishing new analyses and the total analysis time by up to 90%. On the other hand, both approaches showed similar quantitative results in plaque and activated microglia density in the different experimental groups. DeePathology STUDIO showed higher sensitivity and accuracy for small-sized plaques. In addition, DeePathology STUDIO allowed the classification of plaques in diffuse- and dense-packed, which was not possible with our traditional analysis. Conclusion: DeePathology STUDIO substantially reduced the effort needed for a new analysis showing comparable quantitative results to the traditional approach. In addition, it allowed including different objects (categories) or cell types in a single analysis, which is not possible with conventional methods.

• Möhle, Luisa; Brackhan, Mirjam; Almarcha, Pablo Bascuñana & Pahnke, Jens (2021). Dimethyl fumarate does not mitigate cognitive decline and β-amyloidosis in female APPPS1 mice. Brain Research. ISSN 0006-8993. 1768:147579, s. 1–9. doi: 10.1016/j.brainres.2021.147579. Fulltekst i vitenarkiv Vis sammendrag

  Introduction Alzheimer’s disease (AD) is the leading cause of dementia and a major global health issue. Currently, only limited treatment options are available to patients. One possibility to expand the treatment repertoire is repurposing of existing drugs such as dimethyl fumarate (DMF). DMF is approved for treatment of multiple sclerosis and previous animal studies have suggested that DMF may also have a beneficial effect for the treatment of AD. Methods We used an APPPS1 transgenic model of senile β-amyloidosis and treated female mice orally with DMF in two treatment paradigms (pre and post onset). We quantified learning and memory parameters, β-amyloidosis, and neuroinflammation to determine the potential of DMF as AD therapeutics. Results Treatment with DMF had no influence on water maze performance, β-amyloid accumulation, plaque formation, microglia activation, and recruitment of immune cells to the brain. Compared to vehicle-treated animals, oral DMF treatment could not halt or retard disease progression in the mice. Discussion Our results do not favour the use of DMF as treatment for AD. While our results stand in contrast to previous findings in other models, they emphasize the importance of animal model selection and suggest further studies to elucidate the mechanisms leading to conflicting results.

• Borovkova, Mariia; Sieryi, Oleksii; Lopushenko, Ivan; Kartashkina, Natalia; Pahnke, Jens & Bykov, Alexander [Vis alle 7 forfattere av denne artikkelen] (2021). Screening of Alzheimer's Disease with Multiwavelength Stokes Polarimetry in a Mouse Model. IEEE Transactions on Medical Imaging. ISSN 0278-0062. 41(4), s. 977–982. doi: 10.1109/TMI.2021.3129700. Fulltekst i vitenarkiv Vis sammendrag

  The minimum histological criterion for the diagnostics of Alzheimer’s disease (AD) in tissue is the presence of senile plaques and neurofibrillary tangles in specific brain locations. The routine procedure of morphological analysis implies time-consuming and laborious steps including sectioning and staining of formalin-fixed paraffin-embedded (FFPE) tissue. We developed a multispectral Stokes polarimetric imaging approach that allows characterization of FFPE brain tissue samples to discern the stages of AD progression without sectioning and staining the tissue. The Stokes polarimetry approach is highly sensitive to structural alterations of brain tissue, particularly to the changes in light scattering and birefringence. We present the results of the label-free non-destructive screening of FFPE mouse brain tissue and show several polarization metrics that demonstrate statistically significant differences for tissues at different stages of AD.

• Namasivayam, Vigneshwaran; Silbermann, Katja; Wiese, Michael; Pahnke, Jens & Stefan, Sven Marcel (2021). C@PA: Computer-Aided Pattern Analysis to Predict Multitarget ABC Transporter Inhibitors. Journal of Medicinal Chemistry. ISSN 0022-2623. 64(6), s. 3350–3366. doi: 10.1021/acs.jmedchem.0c02199. Fulltekst i vitenarkiv Vis sammendrag

  Based on literature reports of the last two decades, a computer-aided pattern analysis (C@PA) was implemented for the discovery of novel multitarget ABCB1 (P-gp), ABCC1 (MRP1), and ABCG2 (BCRP) inhibitors. C@PA included basic scaffold identification, substructure search and statistical distribution, as well as novel scaffold extraction to screen a large virtual compound library. Over 45,000 putative and novel broad-spectrum ABC transporter inhibitors were identified, from which 23 were purchased for biological evaluation. Our investigations revealed five novel lead molecules as triple ABCB1, ABCC1, and ABCG2 inhibitors. C@PA is the very first successful computational approach for the discovery of promiscuous ABC transporter inhibitors.

• Svendsen, Henrik Aasrum; Meling, Torstein Ragnar; Nygaard, Vigdis; Waagene, Stein; Russnes, Hege Elisabeth Giercksky & Juell, Siri [Vis alle 11 forfattere av denne artikkelen] (2021). Novel human melanoma brain metastasis models in athymic nude fox1^nu mice: Site-specific metastasis patterns reflecting their clinical origin. Cancer Medicine. 10(23), s. 8604–8613. doi: 10.1002/cam4.4334. Fulltekst i vitenarkiv Vis sammendrag

  Background: Malignant melanomas frequently metastasize to the brain, but metastases in the cerebellum are underrepresented compared with metastases in the cerebrum.<p> <p>Methods: We established animal models by injecting intracardially in athymic nude fox1^nu mice two human melanoma cell lines, originating from a cerebral metastasis (HM19) and a cerebellar metastasis (HM86).<p> <p>Results: Using magnetic resonance imaging (MRI), metastases were first detected after a mean of 34.5 days. Mean survival time was 59.6 days for the mice in the HM86 group and significantly shorter (43.7 days) for HM19-injected animals (p < 0.001). In the HM86 group, the first detectable metastasis was located in the cerebellum in 15/55 (29%) mice compared with none in the HM19 group (p < 0.001). At sacrifice, cerebellar metastases were found in 34/55 (63%) HM86- injected mice compared with 1/53 (2%) in the HM19-injected (p < 0.001) mice. At that time, all mice in both groups had detectable metastases in the cerebrum. Comparing macroscopic and histologic appearances of the brain metastases with their clinical counterparts, the cell line-based tumors had kept their original morphologic characteristics.<p> <p>Conclusions: The present work demonstrates that human brain-metastatic melanoma cells injected intracardially in mice had retained inherent characteristics also in reproducing interaction with subtle microenvironmental brain tissue compartment-specific features. The models offer new possibilities for investigating tumor- and host-associated factors involved in determining tissue specificity of brain metastasis.

• Möhle, Luisa; Bascuñana, Pablo; Brackhan, Mirjam & Pahnke, Jens (2021). Development of deep learning models for microglia analyses in brain tissue using DeePathology™ STUDIO. Journal of Neuroscience Methods. ISSN 0165-0270. 364:109371, s. 1–9. doi: 10.1016/j.jneumeth.2021.109371. Fulltekst i vitenarkiv Vis sammendrag

  Background Interest in artificial intelligence-driven analysis of medical images has seen a steep increase in recent years. Thus, our paper aims to promote and facilitate the use of this state-of-the-art technology to fellow researchers and clinicians. New method We present custom deep learning models generated in DeePathology™ STUDIO without the need for background knowledge in deep learning and computer science underlined by practical suggestions. Results We describe the general workflow in this commercially available software and present three real-world examples how to detect microglia on IBA1-stained mouse brain sections including their differences, validation results and analysis of a sample slide. Comparison with existing methods Deep-learning assisted analysis of histological images is faster than classical analysis methods, and offers a wide variety of detection possibilities that are not available using methods based on staining intensity. Conclusions Reduced researcher bias, increased speed and extended possibilities make deep-learning assisted analysis of histological images superior to traditional analysis methods for histological images.

• Dib, Shiraz; Pahnke, Jens & Gosselet, Fabien (2021). Role of ABCA7 in Human Health and in Alzheimer’s Disease. International Journal of Molecular Sciences. ISSN 1661-6596. 22:4603(9), s. 1–15. doi: 10.3390/ijms22094603. Fulltekst i vitenarkiv Vis sammendrag

  Several studies, including genome wide association studies (GWAS), have strongly suggested a central role for the ATP-binding cassette transporter subfamily A member 7 (ABCA7) in Alzheimer’s disease (AD). This ABC transporter is now considered as an important genetic determinant for late onset Alzheimer disease (LOAD) by regulating several molecular processes such as cholesterol metabolism and amyloid processing and clearance. In this review we shed light on these new functions and their cross-talk, explaining its implication in brain functioning, and therefore in AD onset and development.

• Namasivayam, Vigneshwaran; Silbermann, Katja; Pahnke, Jens & Wiese, Michael (2021). Scaffold fragmentation and substructure hopping reveal potential, robustness, and limits of computer-aided pattern analysis (C@PA). Computational and Structural Biotechnology Journal. 19, s. 3269–3283. doi: 10.1016/j.csbj.2021.05.018. Fulltekst i vitenarkiv Vis sammendrag

  Computer-aided pattern analysis (C@PA) was recently presented as a powerful tool to predict multitarget ABC transporter inhibitors. The backbone of this computational methodology was the statistical analysis of frequently occurring molecular features amongst a fixed set of reported small-molecules that had been evaluated toward ABCB1, ABCC1, and ABCG2. As a result, negative and positive patterns were elucidated, and secondary positive substructures could be suggested that complemented the multitarget fingerprints. Elevating C@PA to a non-statistical and exploratory level, the concluded secondary positive patterns were extended with potential positive substructures to improve C@PA’s prediction capabilities and to explore its robustness. A small-set compound library of known ABCC1 inhibitors with a known hit rate for triple ABCB1, ABCC1, and ABCG2 inhibition was taken to virtually screen for the extended positive patterns. In total, 846 potential broad-spectrum ABCB1, ABCC1, and ABCG2 inhibitors resulted, from which 10 have been purchased and biologically evaluated. Our approach revealed 4 novel multitarget ABCB1, ABCC1, and ABCG2 inhibitors with a biological hit rate of 40%, but with a slightly lower inhibitory power than derived from the original C@PA. This is the very first report about discovering novel broad-spectrum inhibitors against the most prominent ABC transporters by improving C@PA.

• Djirackor, Luna; Halldórsson, Skarphéðinn; Niehusmann, Pitt; Leske, Henning; Capper, David & Kuschel, Luis P. [Vis alle 12 forfattere av denne artikkelen] (2021). Intraoperative DNA methylation classification of brain tumors impacts neurosurgical strategy. Neuro-Oncology Advances (NOA). 3(1), s. 1–10. doi: 10.1093/noajnl/vdab149. Fulltekst i vitenarkiv Vis sammendrag

  Background Brain tumor surgery must balance the benefit of maximal resection against the risk of inflicting severe damage. The impact of increased resection is diagnosis-specific. However, the precise diagnosis is typically uncertain at surgery due to limitations of imaging and intraoperative histomorphological methods. Novel and accurate strategies for brain tumor classification are necessary to support personalized intraoperative neurosurgical treatment decisions. Here, we describe a fast and cost-efficient workflow for intraoperative classification of brain tumors based on DNA methylation profiles generated by low coverage nanopore sequencing and machine learning algorithms. Methods We evaluated 6 independent cohorts containing 105 patients, including 50 pediatric and 55 adult patients. Ultra-low coverage whole-genome sequencing was performed on nanopore flow cells. Data were analyzed using copy number variation and ad hoc random forest classifier for the genome-wide methylation-based classification of the tumor. Results Concordant classification was obtained between nanopore DNA methylation analysis and a full neuropathological evaluation in 93 of 105 (89%) cases. The analysis demonstrated correct diagnosis in 6/6 cases where frozen section evaluation was inconclusive. Results could be returned to the operating room at a median of 97 min (range 91-161 min). Precise classification of the tumor entity and subtype would have supported modification of the surgical strategy in 12 out of 20 patients evaluated intraoperatively. Conclusion Intraoperative nanopore sequencing combined with machine learning diagnostics was robust, sensitive, and rapid. This strategy allowed DNA methylation-based classification of the tumor to be returned to the surgeon within a timeframe that supports intraoperative decision making.

• Casar-Borota, Olivera; Boldt, Henning Bünsow; Engström, Britt Edén; Andersen, Marianne Skovsager; Baussart, Bertrand & Bengtsson, Daniel [Vis alle 29 forfattere av denne artikkelen] (2021). Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 106(4), s. 1183–1194. doi: 10.1210/clinem/dgaa749. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Context Aggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors. Objective To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs. Design We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored. Results Nine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs. Conclusion ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors.

• Hermansen, Johanne Uthus; Wojcik, Dorota; Robinson, Nina; Pahnke, Jens; Haugland, Hans Kristian & Jamtøy, Ann-Helen [Vis alle 11 forfattere av denne artikkelen] (2021). The Norwegian childhood cancer biobank. Cancer Reports. 0:e1555(8), s. 1–8. doi: 10.1002/cnr2.1555. Fulltekst i vitenarkiv Vis sammendrag

  Background The rapidly expanding era of “omics” research is highly dependent on the availability of quality-proven biological material, especially for rare conditions such as pediatric malignancies. Professional biobanks provide such material, focusing on standardized collection and handling procedures, distinctive quality measurements, traceability of storage conditions, and accessibility. For pediatric malignancies, traditional tumor biobanking is challenging due to the rareness and limited amount of tissue and blood samples. The higher molecular heterogeneity, lower mutation rates, and unique genomic landscapes, however, renders biobanking of this tissue even more crucial. Aim The aim of this study was to test and establish methods for a prospective and centralized biobank for infants, children, and adolescents up to 18 years of age diagnosed with cancer in Norway. Methods Obtain judicial and ethical approvals and administration through a consortium, steering committee, and advisory board. Develop pipelines including SOPs for all aspects in the biobank process, including collection, processing and storing of samples and data, as well of quality controlling, safeguarding, distributing, and transport. Results The childhood cancer biobanking started at Oslo University Hospital in March 2017 and was from 2019 run as a national Norwegian Childhood Cancer Biobank. Informed consent and biological samples are collected regionally and stored centrally. Approximately 12 000 samples from 510 patients and have been included by January 1, 2021, representing a 96% consent and participation rate among our newly diagnosed patients. Conclusion A well-functioning nationwide collection and centralized biobank with standardized procedures and national storage for pediatric malignancies has been established with a high acceptance among families.

• Rai, Surya Prakash; Krohn, Markus & Pahnke, Jens (2020). Early Cognitive Training Rescues Remote Spatial Memory but Reduces Cognitive Flexibility in Alzheimer's Disease Mice. Journal of Alzheimer's Disease. ISSN 1387-2877. 75(4), s. 1301–1317. doi: 10.3233/JAD-200161. Fulltekst i vitenarkiv Vis sammendrag

  Background: Spatial memory dysfunction has been demonstrated in mouse models of Alzheimer’s disease (AD) which is consistent with the clinical finding that the early signature of AD includes difficulties in the formation and/or storage of a memory. A stored memory—a long term memory—can be modulated via process called as memory retrieval that can either lead toward memory reconsolidation or even memory extinction. Objective: We aim to shed light on the fate of the spatial memory during memory reactivation and memory extinction using a water maze task. Methods: In Set-up I, we trained 3-month-old mice (wild-type mice and mice with cerebral β-amyloidosis) and assessed the fate of remote memory after four months of retention interval (RI). In Set-up II, we performed an early-extensive training at 2 months of age, retrained the same mice at 3 months of age, introduced four months of RI, and finally assessed remote spatial memory at 7 months of age. Results: We find in β-amyloidosis mice that memory reactivation problems were detectable at 7 months of age and were alleviated by cognitive overtraining. Similarly, forgetting of remote spatial memory was also minimized by cognitive overtraining. Finally, we show that the cognitive training facilitates the recovery of the reactivated spatial memory while reducing the ability to form new spatial memory in AD mice. Conclusion: This result may explain the rationality behind the cognitive reserve observed in AD patients and elderly with severe β-amyloidosis not corresponding to the actual low dementia symptoms.

• Rai, Surya Prakash; Bascuñana, Pablo; Brackhan, Mirjam; Krohn, Markus; Möhle, Luisa & Paarmann, Kristin [Vis alle 7 forfattere av denne artikkelen] (2020). Detection and Prediction of Mild Cognitive Impairment in Alzheimer's Disease Mice. Journal of Alzheimer's Disease. ISSN 1387-2877. 77(3), s. 1209–1221. doi: 10.3233/JAD-200675. Fulltekst i vitenarkiv Vis sammendrag

  Background: The recent failure of clinical trials to treat Alzheimer’s disease (AD) indicates that the current approach of modifying disease is either wrong or is too late to be efficient. Mild cognitive impairment (MCI) denotes the phase between the preclinical phase and clinical overt dementia. AD mouse models that overexpress human amyloid-β (Aβ) are used to study disease pathogenesis and to conduct drug development/testing. However, there is no direct correlation between the Aβ deposition, the age of onset, and the severity of cognitive dysfunction. Objective: To detect and predict MCI when Aβ plaques start to appear in the hippocampus of an AD mouse. Methods: We trained wild-type and AD mice in a Morris water maze (WM) task with different inter-trial intervals (ITI) at 3 months of age and assessed their WM performance. Additionally, we used a classification algorithm to predict the genotype (APPtg versus wild-type) of an individual mouse from their respective WM data. Results: MCI can be empirically detected using a short-ITI protocol. We show that the ITI modulates the spatial learning of AD mice without affecting the formation of spatial memory. Finally, a simple classification algorithm such as logistic regression on WM data can give an accurate prediction of the cognitive dysfunction of a specific mouse. Conclusion: MCI can be detected as well as predicted simultaneously with the onset of Aβ deposition in the hippocampus in AD mouse model. The mild cognitive impairment prediction can be used for assessing the efficacy of a treatment.

• Kolnes, Anders Jensen; Øystese, Kristin Astrid; Dahlberg, Daniel; Berg-Johnsen, Jon; Niehusmann, Pitt & Pahnke, Jens [Vis alle 8 forfattere av denne artikkelen] (2020). Cut-off values for sufficient cortisol response to low dose Short Synacthen Test after surgery for non-functioning pituitary adenoma. Acta Neurochirurgica. ISSN 0001-6268. 162(4), s. 845–852. doi: 10.1007/s00701-019-04068-z. Fulltekst i vitenarkiv Vis sammendrag

  Objective The aim was to study the prevalence of secondary adrenal insufficiency before and after surgery for non-functioning pituitary adenomas, as well as determine risk factors for developing secondary adrenal insufficiency. A secondary aim was to determine adequate p-cortisol response to a 1-μg Short Synacthen Test after surgery. Design Longitudinal cohort study. Methods One hundred seventeen patients (52/65 females/males, age 59 years) undergoing primary surgery for clinically non-functioning pituitary adenomas were included. P-cortisol was measured in morning blood samples. Three months after surgery, a Short Synacthen Test was performed. Results All tumours were macroadenomas (mean size 26.9 mm, range 13–61 mm). The surgical indications were visual impairment (93), tumour growth (16), pituitary apoplexy (6) and headache (2). Before surgery, 17% of the patients had secondary adrenal insufficiency (SAI), decreasing to 15% 3 months postoperatively. Risk of SAI was increased in patients operated for pituitary apoplexy (p < 0.001), while age, sex, tumour size and complication rate were not different from the remaining cohort. Three months after surgery, all patients with baseline p-cortisol ≥ 172 nmol/l (6.2 μg/dl) and peak p-cortisol during Short Synacthen Test ≥ 320 nmol/l (11.6 μg/dl) tapered cortisone unproblematically. In patients with intact hypothalamic-pituitary-adrenal axis, p-cortisol peaked < 500 nmol/l (18.1 μg/dl) during Short Synacthen Test in 48% of patient. Conclusion Pituitary surgery is safe and transsphenoidal surgery rarely causes new SAI. Relying solely on morning p-cortisol for diagnosing secondary adrenal insufficiency gives false positives and the Short Synacthen Test remains useful. A peak p-cortisol ≥ 320 during (11.6 μg/dl) Short Synacthen Test indicates a sufficient response, while < 309 nmol/l (11.2 μg/dl) indicates secondary adrenal insufficiency.

• Stefan, Katja; Leck, Lionel Yi Wen; Namasivayam, Vigneshwaran; Bascuñana, Pablo; Huang, Michael Li-Hsuan & Riss, Patrick [Vis alle 9 forfattere av denne artikkelen] (2020). Vesicular ATP-binding cassette transporters in human disease: relevant aspects of their organization for future drug development. Future Drug Discovery. 4:FDD51(2), s. 1–8. doi: 10.4155/fdd-2020-0025. Fulltekst i vitenarkiv
• Wanek, Thomas; Zoufal, Viktoria; Brackhan, Mirjam; Krohn, Markus; Mairinger, Severin & Filip, Thomas [Vis alle 11 forfattere av denne artikkelen] (2020). Brain Distribution of Dual ABCB1/ABCG2 Substrates Is Unaltered in a Beta-Amyloidosis Mouse Model. International Journal of Molecular Sciences. ISSN 1661-6596. 21:8245(21), s. 1–16. doi: 10.3390/ijms21218245. Fulltekst i vitenarkiv Vis sammendrag

  Background: ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein) are co-localized at the blood-brain barrier (BBB), where they restrict the brain distribution of many different drugs. Moreover, ABCB1 and possibly ABCG2 play a role in Alzheimer’s disease (AD) by mediating the brain clearance of beta-amyloid (Aβ) across the BBB. This study aimed to compare the abundance and activity of ABCG2 in a commonly used β-amyloidosis mouse model (APP/PS1-21) with age-matched wild-type mice. Methods: The abundance of ABCG2 was assessed by semi-quantitative immunohistochemical analysis of brain slices of APP/PS1-21 and wild-type mice aged 6 months. Moreover, the brain distribution of two dual ABCB1/ABCG2 substrate radiotracers ([11C]tariquidar and [11C]erlotinib) was assessed in APP/PS1-21 and wild-type mice with positron emission tomography (PET). [11C]Tariquidar PET scans were performed without and with partial inhibition of ABCG2 with Ko143, while [11C]erlotinib PET scans were only performed under baseline conditions. Results: Immunohistochemical analysis revealed a significant reduction (by 29–37%) in the number of ABCG2-stained microvessels in the brains of APP/PS1-21 mice. Partial ABCG2 inhibition significantly increased the brain distribution of [11C]tariquidar in APP/PS1-21 and wild-type mice, but the brain distribution of [11C]tariquidar did not differ under both conditions between the two mouse strains. Similar results were obtained with [11C]erlotinib. Conclusions: Despite a reduction in the abundance of cerebral ABCG2 and ABCB1 in APP/PS1-21 mice, the brain distribution of two dual ABCB1/ABCG2 substrates was unaltered. Our results suggest that the brain distribution of clinically used ABCB1/ABCG2 substrate drugs may not differ between AD patients and healthy people.

• Zoufal, Viktoria; Mairinger, Severin; Brackhan, Mirjam; Krohn, Markus; Filip, Thomas & Sauberer, Michael [Vis alle 12 forfattere av denne artikkelen] (2020). Imaging P-Glycoprotein Induction at the Blood-Brain Barrier of a β-Amyloidosis Mouse Model with 11 C-Metoclopramide PET. Journal of Nuclear Medicine. ISSN 0161-5505. 61(7), s. 1050–1057. doi: 10.2967/jnumed.119.237198. Fulltekst i vitenarkiv Vis sammendrag

  P-glycoprotein (ABC subfamily B member 1, ABCB1) plays an important role at the blood–brain barrier (BBB) in promoting clearance of neurotoxic β-amyloid (Aβ) peptides from the brain into the blood. ABCB1 expression and activity were found to be decreased in the brains of Alzheimer disease patients. Treatment with drugs that induce cerebral ABCB1 activity may be a promising approach to delay the build-up of Aβ deposits in the brain by enhancing clearance of Aβ peptides from the brain. The aim of this study was to investigate whether PET with the weak ABCB1 substrate radiotracer 11C-metoclopramide can measure ABCB1 induction at the BBB in a β-amyloidosis mouse model (APP/PS1-21 mice) and in wild-type mice. Methods: Groups of wild-type and APP/PS1-21 mice aged 50 or 170 d underwent 11C-metoclopramide baseline PET scans or scans after intraperitoneal treatment with the rodent pregnane X receptor activator 5-pregnen-3β-ol-20-one-16α-carbonitrile (PCN, 25 mg/kg) or its vehicle over 7 d. At the end of the PET scans, brains were harvested for immunohistochemical analysis of ABCB1 and Aβ levels. In separate groups of mice, radiolabeled metabolites of 11C-metoclopramide were determined in plasma and brain at 15 min after radiotracer injection. As an outcome parameter of cerebral ABCB1 activity, the elimination slope of radioactivity washout from the brain (kE,brain) was calculated. Results: PCN treatment resulted in an increased clearance of radioactivity from the brain as reflected by significant increases in kE,brain (from +26% to +54% relative to baseline). Immunohistochemical analysis confirmed ABCB1 induction in the brains of PCN-treated APP/PS1-21 mice with a concomitant decrease in Aβ levels. There was a significant positive correlation between kE,brain and ABCB1 levels in the brain. In wild-type mice, a significant age-related decrease in kE,brain was found. Metabolite analysis showed that most radioactivity in the brain comprised unmetabolized 11C-metoclopramide in all animal groups. Conclusion: 11C-metoclopramide can measure ABCB1 induction in the mouse brain without the need to consider an arterial input function and may find potential application in Alzheimer disease patients to noninvasively evaluate strategies to enhance the clearance properties of the BBB.

• Möhle, Luisa; Schwarzova, Barbora; Krohn, Markus; Stefan, Sven Marcel & Pahnke, Jens (2020). Using a qPCR device to screen for modulators of ABC transporter activity: A step-by-step protocol. Journal of pharmacological and toxicological methods. ISSN 1056-8719. 104:106882, s. 1–11. doi: 10.1016/j.vascn.2020.106882. Fulltekst i vitenarkiv Vis sammendrag

  Introduction Adenosine triphosphate (ATP)-binding cassette (ABC) transporters are transmembrane proteins which actively transport a large variety of substrates across biological membranes. ABC transporter overexpression can be the underlying cause of multidrug resistance in oncology. Moreover, it has been revealed that increased ABCC1 transporter activity can ameliorate behavioural changes and Aβ pathology in a rodent model of Alzheimer's disease and it is currently tested in AD patients. Methods Finding substances that modulate ABC transporter activity (inhibitors and activators) is of high relevance and thus, different methods have been developed to screen for potential modulators. For this purpose, we have developed a cell-based assay to measure the kinetics of ABCC1-mediated efflux of a fluorescent dye using a common qPCR device (Agilent AriaMx). Results We validated the specificity of our method with vanadate and benzbromarone controls. Furthermore, we provide a step-by-step protocol including statistical analysis of the resulting data and suggestions how to modify the protocol specifically to screen for activators of ABCC1. Discussion Our approach is biologically more relevant than cell-free assays. The continuous detection of kinetics allows for a more precise quantification compared with assays with single end-point measurements.

• Borovkova, Mariia; Bykov, Alexander; Popov, Alexey; Pierangelo, Angelo; Novikova, Tatiana & Pahnke, Jens [Vis alle 7 forfattere av denne artikkelen] (2020). Evaluating β-amyloidosis progression in Alzheimer's disease with Mueller polarimetry. Biomedical Optics Express. 11(8), s. 4509–4519. doi: 10.1364/BOE.396294. Fulltekst i vitenarkiv Vis sammendrag

  We applied the wide-field Mueller imaging polarimetry for the screening of formalin-fixed paraffin-embedded samples of mouse brain tissue at different stages of brain β-amyloidosis in Alzheimer’s disease (AD). The accumulation of amyloid-beta (Aβ) deposits throughout the brain tissue is one of the key pathological hallmarks observed with the AD progression. We demonstrate that the presence of Aβ plaques influences the properties of backscattered polarized light, in particular, its degree of depolarization. By means of statistical analysis, we demonstrate that the high-order statistical moments of depolarization distributions, acquired with the multi-spectral Mueller imaging polarimetry, can be used as sensitive markers of the growing presence of Aβ plaques. The introduced label-free polarimetric approach has a potential to facilitate the current practice of the histopathology screening in terms of diagnosis accuracy, time and cost efficiency. © 2020 Optical Society of America. Users may use, reuse, and build upon the article, or use the article for text or data mining, so long as such uses are for non-commercial purposes and appropriate attribution is maintained. All other rights are reserved.

• Abelein, Axel; Chen, Gefei; Kitoka, Kristine; Alexis, Rihards; Oleskovs, Filips & Sarr, Médoune [Vis alle 14 forfattere av denne artikkelen] (2020). High-yield Production of Amyloid-β Peptide Enabled by a Customized Spider Silk Domain. Scientific Reports. 10:235(1), s. 1–10. doi: 10.1038/s41598-019-57143-x. Fulltekst i vitenarkiv Vis sammendrag

  During storage in the silk gland, the N-terminal domain (NT) of spider silk proteins (spidroins) keeps the aggregation-prone repetitive region in solution at extreme concentrations. We observe that NTs from different spidroins have co-evolved with their respective repeat region, and now use an NT that is distantly related to previously used NTs, for efficient recombinant production of the amyloid-β peptide (Aβ) implicated in Alzheimer’s disease. A designed variant of NT from Nephila clavipes flagelliform spidroin, which in nature allows production and storage of β-hairpin repeat segments, gives exceptionally high yields of different human Aβ variants as a solubility tag. This tool enables efficient production of target peptides also in minimal medium and gives up to 10 times more isotope-labeled monomeric Aβ peptides per liter bacterial culture than previously reported.

• Borovkova, Mariia; Bykov, Alexander; Popov, Alexey; Pierangelo, Angelo; Novikova, Tatiana & Pahnke, Jens [Vis alle 7 forfattere av denne artikkelen] (2020). The use of Stokes-Mueller polarimetry for assessment of amyloid-β progression in a mouse model of Alzheimer’s disease. Proceedings of SPIE, the International Society for Optical Engineering. ISSN 0277-786X. 11234:112340M, s. 1–6. doi: 10.1117/12.2550795. Fulltekst i vitenarkiv Vis sammendrag

  Alzheimer’s disease, being a major societal burden, demands improvement of current techniques for its treatment and diagnostics. Currently only autopsy histology is able to provide the definite diagnosis for Alzheimer’s disease. However, the procedure is rather time consuming and costly. In the current study, we utilized Stokes and Mueller polarimetry techniques to screen for amyloid-β (Aβ) deposits in formalin-fixed, paraffin-embedded mouse brain tissue at different stages of Alzheimer’s disease. The study has shown that the presence of Aβ plaques influences the properties of scattered polarized light. The Poincaré sphere was used as a graphical tool for the visualization of the alterations of the Stokes vector, obtained with Stokes polarimetry, whereas statistical moments were used for the analysis of depolarization distributions that were acquired with Mueller polarimetry. We demonstrate the sensitivity of the last component of the Stokes vector, the degree of polarization and high-order statistical moments of depolarization to the structural alterations in brain tissue, which correspond to the disease progression. The described approach has a potential to improve the existing pathology screening methods and facilitates Aβ detection in AD research.

• Bascuñana, Pablo; Möhle, Luisa; Brackhan, Mirjam & Pahnke, Jens (2020). Fingolimod as a Treatment in Neurologic Disorders Beyond Multiple Sclerosis. Drugs in R&D. ISSN 1174-5886. 20(3), s. 197–207. doi: 10.1007/s40268-020-00316-1. Fulltekst i vitenarkiv Vis sammendrag

  Fingolimod is an approved treatment for relapsing–remitting multiple sclerosis (MS), and its properties in different pathways have raised interest in therapy research for other neurodegenerative diseases. Fingolimod is an agonist of sphingosine-1-phosphate (S1P) receptors. Its main pharmacologic effect is immunomodulation by lymphocyte homing, thereby reducing the numbers of T and B cells in circulation. Because of the ubiquitous expression of S1P receptors, other effects have also been described. Here, we review preclinical experiments evaluating the effects of treatment with fingolimod in neurodegenerative diseases other than MS, such as Alzheimer’s disease or epilepsy. Fingolimod has shown neuroprotective effects in different animal models of neurodegenerative diseases, summarized here, correlating with increased brain-derived neurotrophic factor and improved disease phenotype (cognition and/or motor abilities). As expected, treatment also induced reductions in different neuroinflammatory markers because of not only inhibition of lymphocytes but also direct effects on astrocytes and microglia. Furthermore, fingolimod treatment exhibited additional effects for specific neurodegenerative disorders, such as reduction of amyloid-β production, and antiepileptogenic properties. The neuroprotective effects exerted by fingolimod in these preclinical studies are reviewed and support the translation of fingolimod into clinical trials as treatment in neurodegenerative diseases beyond neuroinflammatory conditions (MS).

• Zoufal, Viktoria; Mairinger, Severin; Krohn, Markus; Wanek, Thomas; Filip, Thomas & Sauberer, Michael [Vis alle 10 forfattere av denne artikkelen] (2019). Measurement of cerebral ABCC1 transport activity in wild-type and APP/PS1-21 mice with positron emission tomography. Journal of Cerebral Blood Flow and Metabolism. ISSN 0271-678X. 40(5), s. 954–965. doi: 10.1177/0271678X19854541. Fulltekst i vitenarkiv Vis sammendrag

  Previous data suggest a possible link between multidrug resistance-associated protein 1 (ABCC1) and brain clearance of beta-amyloid (Aβ). We used PET with 6-bromo-7-[11C]methylpurine ([11C]BMP) to measure cerebral ABCC1 transport activity in a beta-amyloidosis mouse model (APP/PS1-21) and in wild-type mice aged 50 and 170 days, without and with pretreatment with the ABCC1 inhibitor MK571. One hundred seventy days-old-animals additionally underwent [11C]PiB PET scans to measure Aβ load. While baseline [11C]BMP PET scans detected no differences in the elimination slope of radioactivity washout from the brain (kelim) between APP/PS1-21 and wild-type mice of both age groups, PET scans after MK571 pretreatment revealed significantly higher kelim values in APP/PS1-21 mice than in wild-type mice aged 170 days, suggesting increased ABCC1 activity. The observed increase in kelim occurred across all investigated brain regions and was independent of the presence of Aβ plaques measured with [11C]PiB. Western blot analysis revealed a trend towards increased whole brain ABCC1 levels in 170 days-old-APP/PS1-21 mice versus wild-type mice and a significant positive correlation between ABCC1 levels and kelim. Our data point to an upregulation of ABCC1 in APP/PS1-21 mice, which may be related to an induction of ABCC1 in astrocytes as a protective mechanism against oxidative stress.

• Latysheva, Anna; Emblem, Kyrre Eeg; Brandal, Petter; Vik-Mo, Einar O.; Pahnke, Jens & Røysland, Kjetil [Vis alle 8 forfattere av denne artikkelen] (2019). Dynamic susceptibility contrast and diffusion MR imaging identify oligodendroglioma as defined by the 2016 WHO classification for brain tumors: histogram analysis approach. Neuroradiology. ISSN 0028-3940. 61(5), s. 545–555. doi: 10.1007/s00234-019-02173-5. Fulltekst i vitenarkiv Vis sammendrag

  Purpose According to the revised World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) of 2016, oligodendrogliomas are now defined primarily by a specific molecular signature (presence of IDH mutation and 1p19q codeletion). The purpose of our study was to assess the value of dynamic susceptibility contrast MR imaging (DSC-MRI) and diffusion-weighted imaging (DWI) to characterize oligodendrogliomas and to distinguish them from astrocytomas. Methods Seventy-one adult patients with untreated WHO grade II and grade III diffuse infiltrating gliomas and known 1p/19q codeletion status were retrospectively identified and analyzed using relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) maps based on whole-tumor volume histograms. The Mann-Whitney U test and logistic regression were used to assess the ability of rCBV and ADC to differentiate between oligodendrogliomas and astrocytomas both independently, but also related to the WHO grade. Prediction performance was evaluated in leave-one-out cross-validation (LOOCV). Results Oligodendrogliomas showed significantly higher microvascularity (higher rCBVMean ≥ 0.80, p = 0.013) and higher vascular heterogeneity (lower rCBVPeak ≤ 0.044, p = 0.015) than astrocytomas. Diffuse gliomas with higher cellular density (lower ADCMean ≤ 1094 × 10−6 mm2/s, p = 0.009) were more likely to be oligodendrogliomas than astrocytomas. Histogram analysis of rCBV and ADC was able to differentiate between diffuse astrocytomas (WHO grade II) and anaplastic astrocytomas (WHO grade III). Conclusion Histogram-derived rCBV and ADC parameter may be used as biomarkers for identification of oligodendrogliomas and may help characterize diffuse gliomas based upon their genetic characteristics. Keywords Diffuse glioma Perfusion MRI Diffusion MRI

• Krohn, Markus; Zoufal, Viktoria; Mairinger, Severin; Wanek, Thomas; Paarmann, Kristin & Brüning, Thomas [Vis alle 10 forfattere av denne artikkelen] (2019). Generation and characterization of an ABCC1 humanized mouse model (hABCC1(flx/flx) with knockout capability. Molecular Pharmacology. ISSN 0026-895X. 96(2), s. 138–147. doi: 10.1124/mol.119.115824. Fulltekst i vitenarkiv
• Ceafalan, Laura Cristina; Fertig, Tudor Emanuel; Gheorghe, Teodora Cristina; Hinescu, Mihail Eugen; Popescu, Bogdan Ovidiu & Pahnke, Jens [Vis alle 7 forfattere av denne artikkelen] (2018). Age‐related ultrastructural changes of the basement membrane in the mouse blood‐brain barrier. Journal of Cellular and Molecular Medicine. ISSN 1582-1838. 23(2), s. 819–827. doi: 10.1111/jcmm.13980. Fulltekst i vitenarkiv Vis sammendrag

  The blood‐brain barrier (BBB) is essential for a functional neurovascular unit. Most studies focused on the cells forming the BBB, but very few studied the basement membrane (BM) of brain capillaries in ageing. We used transmission electron microscopy and electron tomography to investigate the BM of the BBB in ageing C57BL/6J mice. The thickness of the BM of the BBB from 24‐month‐old mice was double as compared with that of 6‐month‐old mice (107 nm vs 56 nm). The aged BBB showed lipid droplets gathering within the BM which further increased its thickness (up to 572 nm) and altered its structure. The lipids appeared to accumulate toward the glial side of the BM. Electron tomography showed that the lipid‐rich BM regions are located in small pockets formed by the end‐feet of astrocytes. These findings suggest an imbalance of the lipid metabolism and that may precede the structural alteration of the BM. These alterations may favour the accretion of abnormal proteins that lead to neurodegeneration in ageing. These findings warrant further investigation of the BM of brain capillaries and of adjoining cells as potential targets for future therapies.

• Leske, Henning; Rushing, Elisabeth; Budka, Herbert; Niehusmann, Pitt; Pahnke, Jens & Panagopoulos, Ioannis (2018). K27/G34 versus K28/G35 in histone H3-mutant gliomas: A note of caution. Acta Neuropathologica. ISSN 0001-6322. 136, s. 175–176. doi: 10.1007/s00401-018-1867-2. Fulltekst i vitenarkiv
• Krohn, Markus; Wanek, Thomas; Menet, Marie-Claude; Noack, Andreas; Declèves, Xavier & Langer, Oliver [Vis alle 8 forfattere av denne artikkelen] (2018). Humanization of the Blood-Brain Barrier Transporter ABCB1 in Mice Disrupts Genomic Locus - Lessons from Three Unsuccessful Approaches. European Journal of Microbiology and Immunology. ISSN 2062-509X. 8(3), s. 78–86. doi: 10.1556/1886.2018.00008. Fulltekst i vitenarkiv Vis sammendrag

  ATP-binding cassette (ABC) transporters are of major importance for the restricted access of toxins and drugs to the human body. At the body's barrier tissues like the blood–brain barrier, these transporters are highly represented. Especially, ABCB1 (P-glycoprotein) has been a priority target of pharmaceutical research, for instance, to aid chemotherapy of cancers, therapy resistant epilepsy, and lately even neurodegenerative diseases. To improve translational research, the humanization of mouse genes has become a popular tool although, like recently seen for Abcb1, not all approaches were successful. Here, we report the characterization of another unsuccessful commercially available ABCB1 humanized mouse strain. In vivo assessment of transporter activity using positron emission tomography imaging revealed a severe reduction of ABCB1 function in the brain of these mice. Analyses of brain mRNA and protein expression showed that the murine Abcb1a gene is still expressed in homozygous humanized animals while expression of the human gene is minimal. Promoter region analyses underpinned that the introduced human gene might dysregulate normal expression and provided insights into the regulation of both transcription and translation of Abcb1a. We conclude that insertion of the human coding DNA sequence (CDS) into exon 3 instead of exon 2 most probably represents a more promising strategy for Abcb1a humanization.

• Chee, Yuemin Celina; Pahnke, Jens; Bunte, Ralph; Adsool, Vikrant A; Madan, Babita & Virshup, David M (2018). Intrinsic Xenobiotic Resistance of the Intestinal Stem Cell Niche. Developmental Cell. ISSN 1534-5807. 46(6), s. 681–695.e5. doi: 10.1016/j.devcel.2018.07.023. Fulltekst i vitenarkiv Vis sammendrag

  The gut absorbs dietary nutrients and provides a barrier to xenobiotics and microbiome metabolites. To cope with toxin exposures, the intestinal epithelium is one of the most rapidly proliferating tissues in the body. The stem cell niche supplies essential signaling factors including Wnt proteins secreted by subepithelial myofibroblasts. Unexpectedly, therapeutically effective doses of orally administered PORCN inhibitors that block all Wnt secretion do not affect intestinal homeostasis. We find that intestinal myofibroblasts are intrinsically resistant to multiple xenobiotics, including PORCN inhibitors and the anthracycline antibiotic doxorubicin. These myofibroblasts have high expression of a subset of drug transporters; knockout of Mrp1/Abcc1 enhances drug sensitivity. Tamoxifen administration to Rosa26CreERT2;mT/mG mice visually highlights the drug-resistant intestinal stromal compartment and identifies small populations of drug-resistant cells in lung, kidney, and pancreatic islets. Xenobiotic resistance of the Wnt-producing myofibroblasts can protect the intestinal stem cell niche in the face of an unpredictable environment.

• Latysheva, Anna; Emblem, Kyrre Eeg; Server, Andrés; Brandal, Petter; Meling, Torstein Ragnar & Pahnke, Jens [Vis alle 7 forfattere av denne artikkelen] (2018). Survival associations using perfusion and diffusion magnetic resonance imaging in patients with histologic and genetic defined diffuse glioma World Health Organization grades II and III. Journal of computer assisted tomography. ISSN 0363-8715. 42(5), s. 807–815. doi: 10.1097/RCT.0000000000000742. Fulltekst i vitenarkiv Vis sammendrag

  Objective: According to the new World Health Organization 2016 classification for tumors of the central nervous system, 1p/19q codeletion defines the genetic hallmark that differentiates oligodendrogliomas from diffuse astrocytomas. The aim of our study was to evaluate whether relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) histogram analysis can stratify survival in adult patients with genetic defined diffuse glioma grades II and III. Methods: Sixty-seven patients with untreated diffuse gliomas World Health Organization grades II and III and known 1p/19q codeletion status were included retrospectively and analyzed using ADC and rCBV maps based on whole-tumor volume histograms. Overall survival and progression-free survival (PFS) were analyzed by using Kaplan-Meier and Cox survival analyses adjusted for known survival predictors. Results: Significant longer PFS was associated with homogeneous rCBV distribution–higher rCBVpeak (median, 37 vs 26 months; hazard ratio [HR], 3.2; P = 0.02) in patients with astrocytomas, and heterogeneous rCBV distribution–lower rCBVpeak (median, 46 vs 37 months; HR, 5.3; P < 0.001) and higher rCBVmean (median, 44 vs 39 months; HR, 7.9; P = 0.003) in patients with oligodendrogliomas. Apparent diffusion coefficient parameters (ADCpeak, ADCmean) did not stratify PFS and overall survival. Conclusions: Tumors with heterogeneous perfusion signatures and high average values were associated with longer PFS in patients with oligodendrogliomas. On the contrary, heterogeneous perfusion distribution was associated with poor outcome in patients with diffuse astrocytomas.

• Zoufal, Viktoria; Mairinger, Severin; Krohn, Markus; Wanek, Thomas; Filip, Thomas & Sauberer, Michael [Vis alle 12 forfattere av denne artikkelen] (2018). Influence of Multidrug Resistance-Associated Proteins on the Excretion of the ABCC1 Imaging Probe 6-Bromo-7-[(11)C]Methylpurine in Mice. Molecular Imaging and Biology. ISSN 1536-1632. s. 1–11. doi: 10.1007/s11307-018-1230-y. Fulltekst i vitenarkiv
• Mairinger, Severin; Zoufal, Viktoria; Wanek, Thomas; Traxl, Alexander; Filip, Thomas & Sauberer, Michael [Vis alle 11 forfattere av denne artikkelen] (2018). Influence of breast cancer resistance protein and P-glycoprotein on tissue distribution and excretion of Ko143 assessed with PET imaging in mice. European Journal of Pharmaceutical Sciences. ISSN 0928-0987. 115, s. 212–222. doi: 10.1016/j.ejps.2018.01.034. Fulltekst i vitenarkiv
• Zoufal, Viktoria; Wanek, Thomas; Krohn, Markus; Mairinger, Severin; Filip, Thomas & Sauberer, Michael [Vis alle 11 forfattere av denne artikkelen] (2018). Age dependency of cerebral P-glycoprotein function in wild-type and APPPS1 mice measured with PET. Journal of Cerebral Blood Flow and Metabolism. ISSN 0271-678X. 40(1), s. 150–162. doi: 10.1177/0271678X18806640. Fulltekst i vitenarkiv
• Steffen, Johannes; Stenzel, Jan; Ibrahim, Saleh & Pahnke, Jens (2018). Short-Term Effects of Microglia-Specific Mitochondrial Dysfunction on Amyloidosis in Transgenic Models of Alzheimer's Disease. Journal of Alzheimer's Disease. ISSN 1387-2877. 65(2), s. 465–474. doi: 10.3233/JAD-180395. Fulltekst i vitenarkiv Vis sammendrag

  Reduction of mitochondrial activity is a subtle and early event in the pathogenesis of Alzheimer’s disease. Mitochondrial damage and consequentially enhanced production of reactive oxygen species is particularly occurring in the vicinity of amyloid plaques. Since all cells are affected by mitochondrial damage, analyses of cell type-specific effects are challenging. To study the impact of mitochondrial alterations on microglial activity in a homogeneous genetic background, we generated bone marrow chimeras of irradiated 46-days-old APP-transgenic mice. For reconstitution, bone marrow from CX3CR1-eGFP mice with mitochondria of either non-obese diabetic or C57BL/6J animals was utilized. Successful reconstitution was evident in 100-day-old animals, by the presence of eGFP-positive cells in liver and spleen. In the brain, one-third of IBA1-positive microglia cells were newly recruited eGFP-expressing cells. Although donor-derived microglia were equally located in the proximity of amyloid plaques, no difference was observed in either the amyloid level, total number, or microglial coverage of plaques. These results indicate that during this brief and early phase of amyloid deposition, beneficial mitochondrial alterations in the newly recruited third of microglial cells were not sufficient to affect the amyloidosis in APP-transgenic mice. © 2018 IOS Press

• Paarmann, Kristin; Prakash, Sanjeev; Krohn, Markus; Möhle, Luisa; Brackhan, Mirjam & Brüning, Thomas [Vis alle 8 forfattere av denne artikkelen] (2018). French maritime pine bark treatment decelerates plaque development and improves spatial memory in Alzheimer's disease mice. Phytomedicine. ISSN 0944-7113. 57, s. 39–48. doi: 10.1016/j.phymed.2018.11.033. Fulltekst i vitenarkiv
• Lamartinière, Yordenca; Boucau, Marie-Christine; Dehouck, Lucie; Krohn, Markus; Pahnke, Jens & Candela, Pietra [Vis alle 8 forfattere av denne artikkelen] (2018). ABCA7 Downregulation Modifies Cellular Cholesterol Homeostasis and Decreases Amyloid-β Peptide Efflux in an in vitro Model of the Blood-Brain Barrier. Journal of Alzheimer's Disease. ISSN 1387-2877. 64(4), s. 1195–1211. doi: 10.3233/JAD-170883. Fulltekst i vitenarkiv
• Storck, Steffen E.; Hartz, Anika M.S.; Bernard, Jessica; Wolf, Andreas; Kachlmeier, André & Mahringer, Anne [Vis alle 9 forfattere av denne artikkelen] (2018). The concerted amyloid-beta clearance of LRP1 and ABCB1/P-gp across the blood-brain barrier is linked by PICALM. Brain, Behavior, and Immunity. ISSN 0889-1591. 73, s. 21–33. doi: 10.1016/j.bbi.2018.07.017. Fulltekst i vitenarkiv
• Steffen, Johannes; Krohn, Markus; Schwitlick, christina; Brüning, Thomas; Paarmann, Kristin & Pietrzik, Claus U [Vis alle 10 forfattere av denne artikkelen] (2017). Expression of endogenous mouse APP modulates β-amyloid deposition in hAPP-transgenic mice. Acta neuropathologica communications. 5(1). doi: 10.1186/s40478-017-0448-2. Fulltekst i vitenarkiv Vis sammendrag

  Amyloid-β (Aβ) deposition is one of the hallmarks of the amyloid hypothesis in Alzheimer’s disease (AD). Mouse models using APP-transgene overexpression to generate amyloid plaques have shown to model only certain parts of the disease. The extent to which the data from mice can be transferred to man remains controversial. Several studies have shown convincing treatment results in reducing Aβ and enhancing cognition in mice but failed totally in human. One model-dependent factor has so far been almost completely neglected: the endogenous expression of mouse APP and its effects on the transgenic models and the readout for therapeutic approaches. Here, we report that hAPP-transgenic models of amyloidosis devoid of endogenous mouse APP expression (mAPP-knockout / mAPPko) show increased amounts and higher speed of Aβ deposition than controls with mAPP. The number of senile plaques and the level of aggregated hAβ were elevated in mAPPko mice, while the deposition in cortical blood vessels was delayed, indicating an alteration in the general aggregation propensity of hAβ together with endogenous mAβ. Furthermore, the cellular response to Aβ deposition was modulated: mAPPko mice developed a pronounced and age-dependent astrogliosis, while microglial association to amyloid plaques was diminished. The expression of human and murine aggregation-prone proteins with differing amino acid sequences within the same mouse model might not only alter the extent of deposition but also modulate the route of pathogenesis, and thus, decisively influence the study outcome, especially in translational research.

• Aleksis, Rihards; Oleskovs, Filips; Jaudzems, Kristaps; Pahnke, Jens & Biverstål, Henrik (2017). Structural studies of amyloid-β peptides: Unlocking the mechanism of aggregation and the associated toxicity. Biochimie. ISSN 0300-9084. 140, s. 176–192. doi: 10.1016/j.biochi.2017.07.011. Fulltekst i vitenarkiv
• Sike, Adam; Wengenroth, Jonas; Upite, Jolanta; Brüning, Thomas; Delgado, Iván Eiriz & Santha, Petra [Vis alle 11 forfattere av denne artikkelen] (2017). Improved method for cannula fixation for long-term intracerebral brain infusion. Journal of Neuroscience Methods. ISSN 0165-0270. 290, s. 145–150. doi: 10.1016/j.jneumeth.2017.07.026. Fulltekst i vitenarkiv
• Hofrichter, Jacqueline; Krohn, Markus; Schumacher, Toni; Lange, Cathleen; Feistel, Björn & Walbroel, Bernd [Vis alle 7 forfattere av denne artikkelen] (2016). Sideritis spp. extracts enhance memory and learning in Alzheimer's β-amyloidosis mouse models and aged C57Bl/6 mice. Journal of Alzheimer's Disease. ISSN 1387-2877. 53(3), s. 967–980. doi: 10.3233/JAD-160301. Fulltekst i vitenarkiv
• Möhle, Luisa; Israel, Nicole; Paarmann, Kristin; Krohn, Markus; Pietkiewicz, Sabine & Müller, Andreas [Vis alle 15 forfattere av denne artikkelen] (2016). Chronic Toxoplasma gondii infection enhances β-amyloid phagocytosis and clearance by recruited monocytes. Acta neuropathologica communications. 4. doi: 10.1186/s40478-016-0293-8. Fulltekst i vitenarkiv
• Marques, Fernanda; Sousa, Joao Carlos; Brito, Maria Alexandra; Pahnke, Jens; Santos, Cecilia & Correia-Neves, Margarida [Vis alle 7 forfattere av denne artikkelen] (2016). The choroid plexus in health and in disease: dialogues into and out of the brain. Neurobiology of Disease. ISSN 0969-9961. s. 32–40. doi: 10.1016/j.nbd.2016.08.011. Fulltekst i vitenarkiv
• Steffen, Johannes; Krohn, Markus; Paarmann, Kristin; Schwitlick, christina; Brüning, Thomas & Marreiros, Rita [Vis alle 10 forfattere av denne artikkelen] (2016). Revisiting rodent models: Octodon degus as Alzheimer's disease model? Acta neuropathologica communications. 5(49). doi: 10.1186/s40478-016-0363-y. Fulltekst i vitenarkiv Vis sammendrag

  Alzheimer’s disease primarily occurs as sporadic disease and is accompanied with vast socio-economic problems. The mandatory basic research relies on robust and reliable disease models to overcome increasing incidence and emerging social challenges. Rodent models are most efficient, versatile, and predominantly used in research. However, only highly artificial and mostly genetically modified models are available. As these ‘engineered’ models reproduce only isolated features, researchers demand more suitable models of sporadic neurodegenerative diseases. One very promising animal model was the South American rodent Octodon degus, which was repeatedly described as natural ‘sporadic Alzheimer’s disease model’ with ‘Alzheimer’s disease-like neuropathology’. To unveil advantages over the ‘artificial’ mouse models, we re-evaluated the age-dependent, neurohistological changes in young and aged Octodon degus (1 to 5-years-old) bred in a wild-type colony in Germany. In our hands, extensive neuropathological analyses of young and aged animals revealed normal age-related cortical changes without obvious signs for extensive degeneration as seen in patients with dementia. Neither significant neuronal loss nor enhanced microglial activation were observed in aged animals. Silver impregnation methods, conventional, and immunohistological stains as well as biochemical fractionations revealed neither amyloid accumulation nor tangle formation. Phosphoepitope-specific antibodies against tau species displayed similar intraneuronal reactivity in both, young and aged Octodon degus. In contrast to previous results, our study suggests that Octodon degus born and bred in captivity do not inevitably develop cortical amyloidosis, tangle formation or neuronal loss as seen in Alzheimer’s disease patients or transgenic disease models.

• Bernstein, Hans-Gert; Hildebrandt, Jens; Dobrowolny, Henrik; Steiner, J.; Bogerts, Bernhard & Pahnke, Jens (2016). Morphometric analysis of the cerebral expression of ATP-binding cassette transporter protein ABCB1 in chronic schizophrenia: Circumscribed deficits in the habenula. Schizophrenia Research. ISSN 0920-9964. 177(1-3), s. 52–58. doi: 10.1016/j.schres.2016.02.036. Fulltekst i vitenarkiv
• Fröhlich, Christina; Zschiebsch, Katja; Gröger, Victoria; Paarmann, Kristin; Steffen, Johannes & Thurm, Christoph [Vis alle 15 forfattere av denne artikkelen] (2015). Activation of Mitochondrial Complex II-Dependent Respiration Is Beneficial for α-Synucleinopathies. Molecular Neurobiology. ISSN 0893-7648. Published ahead of print. doi: 10.1007/s12035-015-9399-4. Fulltekst i vitenarkiv Vis sammendrag

  Parkinson ’ s disease and dementia with Lewy bodies are major challenges in research and clinical medicine world-wide and contribute to the most com- mon neurodegenerative disorders. Previously, specific mitochondrial polymorphisms have been found to en- hance clearance of amyloid- β from the brain of APP- transgenic mice leading to beneficial clinical outcome. It has been discussed whether sp ecific mitochondrial alter- ations contribute to disease p rogression or even prevent toxic peptide deposition, as seen in many neurodegener- ative diseases. Here, we investigated α -synuclein- transgenic C57BL/6J mice with the A30P mutation, and a novel A30P C57BL/6J mouse model with three mitochondrial DNA polymorphisms in the ND3, COX3 and mtRNA Arg genes, as found in the inbred NOD/LtJ mouse strain. We were able to detect that the new mod- el has increased mitochondrial complex II-respiration which occurs in parallel to neuronal loss and improved motor performance, although it exhibits higher amounts of high molecular weight species of α -synuclein. High molecular weight aggregates of different peptides are controversially discussed in the light of neurodegenera- tion. A favourable hypothesis states that high molecular weight species are protective and of minor importance for the pathogenesis of neurodegenerative disorders as compared to the extreme neurotoxic monomers and olig- omers. Summarising, our results point to a potentially protective and beneficial effect of specific mitochondrial polymorphisms which cause improved mitochondrial complex II-respiration in α -synucleinopathies, an effect that could be exploited further for pharmaceutical interventions.

• Lill, Christina M.; Rengmark, Aina Sylvia Haugen; Pihlstrøm, Lasse; Fogh, Isabella; Shatunov, Aleksey & Sleiman, Patrick M. [Vis alle 51 forfattere av denne artikkelen] (2015). The role of TREM2 R47H as a risk factor for Alzheimer’s disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson’s disease. Alzheimer's & Dementia. ISSN 1552-5260. 11(12), s. 1407–1416. doi: 10.1016/j.jalz.2014.12.009. Fulltekst i vitenarkiv
• Apostolova, Ivayla; Niedzielska, Dagmara; Derlin, Thorsten; Koziolek, Eva J.; Amthauer, Holger & Salmen, Benedikt [Vis alle 10 forfattere av denne artikkelen] (2015). Perfusion single photon emission computed tomography in a mouse model of neurofibromatosis type 1: Towards a biomarker of neurologic deficits. Journal of Cerebral Blood Flow and Metabolism. ISSN 0271-678X. 35(8), s. 1304–1312. doi: 10.1038/jcbfm.2015.43. Fulltekst i vitenarkiv
• Budworth, Helen; Harris, Faye R.; Williams, Paul; Lee, Do Yup; Holt, Amy & Pahnke, Jens [Vis alle 10 forfattere av denne artikkelen] (2015). Suppression of somatic expansion delays the onset of pathophysiology in a mouse model of Huntington’s disease. PLoS Genetics. ISSN 1553-7390. 11:e1005267(8). doi: 10.1371/journal.pgen.1005267. Fulltekst i vitenarkiv
• Wanek, Thomas; Römermann, Kerstin; Mairinger, Severin; Stanek, Johann; Sauberer, Michael & Filip, Thomas [Vis alle 14 forfattere av denne artikkelen] (2015). Factors governing P-glycoprotein-mediated drug-drug interactions at the blood-brain barrier measured with positron emission tomography. Molecular Pharmaceutics. ISSN 1543-8384. 12(9), s. 3214–3225. doi: 10.1021/acs.molpharmaceut.5b00168. Fulltekst i vitenarkiv

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• Hanrieder, Jörg; Sun, Ramon; Ellis, Shane R.; Pahnke, Jens & Savas, Jeffrey N. (2025). Considerations for Spatial Omics, Metabolite Analyses, and Tissue‐Harvesting Artifacts. Journal of Neurochemistry. ISSN 0022-3042. 169(12). doi: 10.1111/jnc.70315. Fulltekst i vitenarkiv Vis sammendrag

  ABSTRACT Within the emerging field of spatial biology, novel analytical technologies are increasingly demonstrated for mapping neurochemical changes in situ. These tools comprise spatial mass spectrometry (MS imaging, MSI), spatial transcriptomics using in situ sequencing, probe‐based spatial omics, as well as laser microdissection and single cell‐type isolation interfaced with either mass spectrometry or next generation RNA sequencing (NGS) for single cell‐type analysis. These approaches significantly exceed the neurochemical methods that are commonly used with respect to molecular specificity and spatial precision. However, despite all these advancements, close attention has still to be paid to appropriate tissue harvesting and enzyme inactivation methods to avoid degradation of neurochemicals and the generation of artifacts, and because of euthanasia or postmortem ischemia. In this editorial, we aim to present the readership with considerations in lieu of emerging analytical and spatial molecular techniques, as well as highlight the relevance of appropriate tissue preparation. Importantly, we discuss different quenching techniques and their compatibility as well as limitations for novel spatial analyses that require morphologically pristine tissues. image

• Moussavi, Nastaran; Azizullah, Hasina; Pahnke, Jens; Malterud, Karl Egil; Inngjerdingen, Kari Tvete & Wangensteen, Helle (2019). Greek mountain tea, a medicinal plant from the Mediterranean countries and Balkan. Fulltekst i vitenarkiv
• Moussavi, Nastaran; Azizullah, Hasina; Pahnke, Jens; Malterud, Karl Egil; Inngjerdingen, Kari Tvete & Wangensteen, Helle (2019). Greek mountain tea, a medicinal plant from Mediterranean countries and Balkan. Fulltekst i vitenarkiv
• Bernstein, Hans-Gert; Hildebrandt, J.; Dobrowolny, Henrik; Steiner, J.; Bogerts, Bernhard & Pahnke, Jens (2018). Corrigendum to 'Morphometric analysis of the cerebral expression of ATP-binding cassette transporter protein ABCB1 in chronic schizophrenia: Circumscribed deficits in the habenula' [Schizophr. Res. 2016 Nov;177(1?3):52?58] (S0920996416300901) (10.1016/j.schres.2016.02.036)). Schizophrenia Research. ISSN 0920-9964. 197, s. 622–623. doi: 10.1016/j.schres.2018.03.036. Fulltekst i vitenarkiv
• Azizullah, Hasina; Pahnke, Jens; Moussavi, Nastaran; Malterud, Karl Egil & Wangensteen, Helle (2018). Gresk fjellte, en medisinplante fra middelhavslandene og Balkan. Fulltekst i vitenarkiv
• Jansone, Baiba; Pahnke, Jens & Biverstål, Henrik (2017). Alcheimera slimības izpētes aktualitātes. Latvijas ārsts. ISSN 1019-5068. s. 48–53. Fulltekst i vitenarkiv
• Mairinger, Severin; Wanek, Thomas; Traxl, Alexander; Krohn, Markus; Stanek, Johann & Filip, Thomas [Vis alle 10 forfattere av denne artikkelen] (2016). 7-[11C]methyl-6-bromopurine, a PET tracer to measure brain Mrp1 function: radiosynthesis and first PET evaluation in mice. 32nd International Austrian Winter Symposium, Zell am See, the Netherlands. 20-23 January 2016. EJNMMI Research. 6(32). doi: 10.1186/s13550-016-0168-9. Fulltekst i vitenarkiv
• Rai, Surya Prakash & Pahnke, Jens (2020). Assessment and modulation of spatial memory in APPPS1-21 mouse model using Morris water maze (Public defence: 09.12.20). Universitetet i Oslo. ISSN 9788283777390. Fulltekst i vitenarkiv

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