Lars Nilsson

Utvalgte publikasjoner

• Jendresen C, Årskog V, Daws MR, Nilsson LNG  (2017) The Alzheimer's disease risk factors apolipoprotein E and TREM2 are linked in a receptor signaling pathway. J Neuroinflammation 14(1):59.
• Henjum K, Almdahl IS, Årskog V, Minthon L, Hansson O, Fladby T, Nilsson LNG (2016) Cerebrospinal fluid soluble TREM2 in aging and Alzheimer's disease. Alzheimers Res Ther. 27;8(1):17.
• Rogeberg M., Almdahl IS., Wettergren M., Nilsson LNG., Fladby T (2015) Isobaric Quantification of Cerebrospinal Fluid Amyloid-β Peptides in Alzheimer's Disease: C-Terminal Truncation Relates to Early Measures of Neurodegeneration. J Proteome Res 14, 4834-43.
• Rogeberg M, Wettergreen M, Nilsson LNG, Fladby T (2015) Identification of amyloid-β mid-domain fragments in human cerebrospinal fluid. Biochimie, 113:86-92.
• Jendresen CB, Cui H, Zhang X, Vlodavsky I, Nilsson LNG, Li JP, (2015) Overexpression of heparanase lowers amyloid burden in AβPP transgenic mice. J Biol. Chem. 290:5053-64.
• Nuruddin S., Syverstad GH., Lillehaug S., Leergaard TB., Nilsson LNG., Ropstad E.,  Krogenæsa A., Haraldsen I., Torp R. (2014) Elevated mRNA-levels of gonadotropin-releasing hormone and its receptor in plaque-bearing Alzheimer´s disease transgenic mice. Plos One 9(8):e103607.
• Lillehaug SD., Syverstad GH., Nilsson LNG., Bjaalie JG., Leergaard TB., Torp R. (2014) Brain-wide distribution and variance of amyloid-beta load in middle aged -transgenic Alzheimer’s disease mice with both the Artic and Swedish AβPP mutations. Neurobiol Aging 35(3):556-64.
• Gumucio A., Lannfelt L., Nilsson LNG (2013) Lack of exon 10 in the murine tau gene results in mild sensorimotor defects with aging. BMC Neurosci. 14:148.
• Lillenes MS., Støen M., Torp R., Nilsson LNG., Günter C-C., Tonjum T. (2013) Transient changes in expression of OGG1, APE1 and PolB in the brains of mice expressing mutant amyloid-β precursor protein (AβPP). Mech. Ageing Dev 134(10):467-77.  
• Philipson O, Lord A, Lalowski M, Soliyman R, Thyberg R, Baumann M, Thyberg J, Bogdanovic N, Olofsson T, Tjernberg L, Ingelsson I, Lannfelt L, Kalimo H and Nilsson LNG (2011) The Arctic mutation results in distinct plaques and accumulation of N- and C-truncated Aβ. Neurobiology of Aging, PMID: 22118948.
• Yang J., Olson L., Nuntagij P., Oguchi T., Camassa LMA, Nilsson LNG, Lannfelt L., Xu Y., Amiry-Moghaddam M., Ottersen OP., Torp R. (2011) Loss of astrocyte polarization in the tg-ArcSwe mouse model of Alzheimer’s disease. Journal Alzheimer’s disease 27(4):711-22.
• Lord A, Philipson P, Klingstedt T, Westermark G, Hammarström P, Nilsson KP and Nilsson LNG (2011) Observations in APP bitransgenic mice suggest that diffuse and compact plaques form by independent processes in Alzheimer’s disease. American Journal of Pathology, 178(5): 2286-2298.
• Codita, A, Gumucio A, Lannfelt L, Gellerfors P, Winblad B, Mohammed A.K, Nilsson LNG (2010) Impaired behavior of female tg-ArcSwe APP mice in the IntelliCage: a longitudinal study. Behav. Brain Research, 215:83-94.
• Philipson O., Lannfelt L. and Nilsson LNG (2009) Genetic and pharmacological evidence of intraneuronal Aβ accumulation in APP transgenic mice. FEBS Lett., 583: 3021-6.
• Lord A., Gumucio-Gatica A., Englund H., Sehlin D., Sundquist V., Söderberg L., Möller C., Gellerfors P., Lannfelt L., Ekholm Pettersson F. and Nilsson LNG (2009) An amyloid-β protofibril-selective antibody prevents amyloid formation in a mouse model of Alzheimer’s disease. Neurobiol. Dis., 36: 425-34.
• Lord A., Englund H., Söderberg L., Tucker S., Clausen F., Hillered L., Gordon MN., Morgan D., Lannfelt L., Ekholm-Pettersson F., Nilsson LNG (2009) Amyloid-β protofibrils correlate with spatial learning in Arctic Alzheimer’s disease transgenic mice. FEBS.J., 276, 995-1006.
• Philipsson O., Hammarström P., Nilsson PKR., Portelius E., Blennow K., Olofsson T., Ingelson M., Hyman BT., Blennow K., Lannfelt L., Kalimo H., Nilsson LNG  (2009) A highly insoluble state of Aβ is found in both Alzheimer´s disease brain and in transgenic mice with the Arctic mutation. Neurobiol. Aging 30:1393-1405.
• Lord A., Kalimo H., Eckman C., Zhang X-Q., Lannfelt L. and Nilsson LNG (2006) The Arctic Alzheimer mutation facilitates early intraneuronal Aβ aggregation and senile plaque formation in transgenic mice. Neurobiol. Aging, 27: 67-77.
• Stenh C., Englund H., Lord A., Johansson A-S., Almeida CG, Gellerfors P., Greengard P., Gouras GK., Lannfelt L., Nilsson LNG (2005) Oligomers of amyloid- are inefficiently measured by ELISA. Ann Neurol., 58: 147-150.
• Nilsson LNG, Arendash GW., Low MA., Leighty RE., Costa DA., Rojiani A., Wu X., Bales KR., Paul SM. and Potter H. (2004) Cognitive impairment in PDAPP mice depends on Apolipoprotein E and ACT-catalyzed amyloid formation. Neurobiol. Aging, 25(9): 1153-67.
• Nilsson LNG, Bales KR., DiCarlo G., Gordon MN., Morgan D., Paul SM. and Potter H. (2001) Alpha-1-antichymotrypsin promotes -sheet amyloid plaque deposition in a transgenic mouse model of Alzheimer’s disease. J. Neurosci., 21(5): 1444-1451.
• Rogers J., Leiter L., McPhee J., Zhan SS., Potter H. and Nilsson LNG (1999) Translation of the Alzheimer’s amyloid precursor protein mRNA is up-regulated by interleukin-1 through 5’ untranslated region sequences. J. Biol. Chem., 274(10): 6421-6431.

• Phan, Tuan Anh; Palm, Pia; Stiphout, Anita van Haaren-van; Graav, Gretchen de; Lea, Marianne & Wøien, Hilde [Vis alle 12 forfattere av denne artikkelen] (2026). Serious gaming as a platform for interprofessional education about the medication process: A curricular resource for students of medicine, pharmacy, and nursing. Journal of Interprofessional Education & Practice. 45, s. 1–6. doi: 10.1016/j.xjep.2026.100846. Fulltekst i vitenarkiv
• Vega, María Pagnon de la; Syvänen, Stina; Giedraitis, Vilmantas; Hooley, Monique; Konstantinidis, Evangelos & Meier, Silvio R. [Vis alle 16 forfattere av denne artikkelen] (2024). Altered amyloid-β structure markedly reduces gliosis in the brain of mice harboring the Uppsala APP deletion. Acta neuropathologica communications. 12:22(1), s. 1–16. doi: 10.1186/s40478-024-01734-x. Fulltekst i vitenarkiv Vis sammendrag

  Deposition of amyloid beta (Aβ) into plaques is a major hallmark of Alzheimer’s disease (AD). Different amyloid precursor protein (APP) mutations cause early-onset AD by altering the production or aggregation properties of Aβ. We recently identified the Uppsala APP mutation (APPUpp), which causes Aβ pathology by a triple mechanism: increased β-secretase and altered α-secretase APP cleavage, leading to increased formation of a unique Aβ conformer that rapidly aggregates and deposits in the brain. The aim of this study was to further explore the effects of APPUpp in a transgenic mouse model (tg-UppSwe), expressing human APP with the APPUpp mutation together with the APPSwe mutation. Aβ pathology was studied in tg-UppSwe brains at different ages, using ELISA and immunohistochemistry. In vivo PET imaging with three different PET radioligands was conducted in aged tg-UppSwe mice and two other mouse models; tg-ArcSwe and tg-Swe. Finally, glial responses to Aβ pathology were studied in cell culture models and mouse brain tissue, using ELISA and immunohistochemistry. Tg-UppSwe mice displayed increased β-secretase cleavage and suppressed α-secretase cleavage, resulting in AβUpp42 dominated diffuse plaque pathology appearing from the age of 5–6 months. The γ-secretase cleavage was not affected. Contrary to tg-ArcSwe and tg-Swe mice, tg-UppSwe mice were [11C]PiB-PET negative. Antibody-based PET with the 3D6 ligand visualized Aβ pathology in all models, whereas the Aβ protofibril selective mAb158 ligand did not give any signals in tg-UppSwe mice. Moreover, unlike the other two models, tg-UppSwe mice displayed a very faint glial response to the Aβ pathology. The tg-UppSwe mouse model thus recapitulates several pathological features of the Uppsala APP mutation carriers. The presumed unique structural features of AβUpp42 aggregates were found to affect their interaction with anti-Aβ antibodies and profoundly modify the Aβ-mediated glial response, which may be important aspects to consider for further development of AD therapies.

• Sulheim, Einar; Widerøe, Marius; Bäck, Marcus; Nilsson, K Peter R; Hammarström, Per & Nilsson, Lars [Vis alle 8 forfattere av denne artikkelen] (2023). Contrast Enhanced Magnetic Resonance Imaging of Amyloid-β Plaques in a Murine Alzheimer's Disease Model. Journal of Alzheimer's Disease. ISSN 1387-2877. 93(2), s. 411–419. doi: 10.3233/JAD-220198. Fulltekst i vitenarkiv Vis sammendrag

  Background: Early detection of amyloid-β (Aβ) aggregates is a critical step to improve the treatment of Alzheimer’s disease (AD) because neuronal damage by the Aβ aggregates occurs before clinical symptoms are apparent. We have previously shown that luminescent conjugated oligothiophenes (LCOs), which are highly specific towards protein aggregates of Aβ, can be used to fluorescently label amyloid plaque in living rodents. Objective: We hypothesize that the LCO can be used to target gadolinium to the amyloid plaque and hence make the plaque detectable by T1-weighted magnetic resonance imaging (MRI). Methods: A novel LCO-gadolinium construct was synthesized to selectively bind to Aβ plaques and give contrast in conventional T1-weighted MR images after intravenous injection in Tg-APPSwe mice. Results: We found that mice with high plaque-burden could be identified using the LCO-Gd constructs by conventional MRI. Conclusion: Our study shows that MR imaging of amyloid plaques is challenging but feasible, and hence contrast-mediated MR imaging could be a valuable tool for early AD detection.

• Zielinski, Mara; Reyes, Fernanda S. Peralta; Gremer, Lothar; Schemmert, Sarah; Frieg, Benedikt & Schäfer, Luisa U. [Vis alle 15 forfattere av denne artikkelen] (2023). Cryo-EM of Aβ fibrils from mouse models find tg-APP<inf>ArcSwe</inf> fibrils resemble those found in patients with sporadic Alzheimer’s disease. Nature Neuroscience. ISSN 1097-6256. 26, s. 2073–2080. doi: 10.1038/s41593-023-01484-4. Fulltekst i vitenarkiv Vis sammendrag

  Abstract The use of transgenic mice displaying amyloid-β (Aβ) brain pathology has been essential for the preclinical assessment of new treatment strategies for Alzheimer’s disease. However, the properties of Aβ in such mice have not been systematically compared to Aβ in the brains of patients with Alzheimer’s disease. Here, we determined the structures of nine ex vivo Aβ fibrils from six different mouse models by cryogenic-electron microscopy. We found novel Aβ fibril structures in the APP/PS1, ARTE10 and tg-SwDI models, whereas the human type II filament fold was found in the ARTE10, tg-APP Swe and APP23 models. The tg-APP ArcSwe mice showed an Aβ fibril whose structure resembles the human type I filament found in patients with sporadic Alzheimer’s disease. A detailed assessment of the Aβ fibril structure is key to the selection of adequate mouse models for the preclinical development of novel plaque-targeting therapeutics and positron emission tomography imaging tracers in Alzheimer’s disease.

• Åbjørsbråten, Knut Sindre; Skaaraas, Gry Helen Enger Syverstad; Cunen, Celine Marie Løken; Bjørnstad, Daniel Marelius; Binder, Kristin Maria Gullestad & Bojarskaite, Laura [Vis alle 15 forfattere av denne artikkelen] (2022). Impaired astrocytic Ca2+ signaling in awake-behaving Alzheimer’s disease transgenic mice. eLIFE. doi: 10.7554/eLife.75055. Fulltekst i vitenarkiv Vis sammendrag

  Increased astrocytic Ca2+ signaling has been shown in Alzheimer’s disease mouse models, but to date no reports have characterized behaviorally induced astrocytic Ca2+ signaling in such mice. Here, we employ an event-based algorithm to assess astrocytic Ca2+ signals in the neocortex of awake-behaving tg-ArcSwe mice and non-transgenic wildtype littermates while monitoring pupil responses and behavior. We demonstrate an attenuated astrocytic Ca2+ response to locomotion and an uncoupling of pupil responses and astrocytic Ca2+ signaling in 15-month-old plaque-bearing mice. Using the genetically encoded fluorescent norepinephrine sensor GRABNE, we demonstrate a reduced norepinephrine signaling during spontaneous running and startle responses in the transgenic mice, providing a possible mechanistic underpinning of the observed reduced astrocytic Ca2+ responses. Our data points to a dysfunction in the norepinephrine–astrocyte Ca2+ activity axis, which may account for some of the cognitive deficits observed in Alzheimer’s disease.

• Vega, María Pagnon De la; Giedraitis, Vilmantas; Michno, Wojciech; Kilander, Lena; Güner, Gökhan & Zielinski, Mara [Vis alle 21 forfattere av denne artikkelen] (2021). The Uppsala APP deletion causes early onset autosomal dominant Alzheimer's disease by altering APP processing and increasing amyloid β fibril formation. Science Translational Medicine. ISSN 1946-6234. 13:eabc6184(606), s. 1–13. doi: 10.1126/scitranslmed.abc6184. Fulltekst i vitenarkiv Vis sammendrag

  Point mutations in the amyloid precursor protein gene (APP) cause familial Alzheimer’s disease (AD) by increasing generation or altering conformation of amyloid β (Aβ). Here, we describe the Uppsala APP mutation (Δ690–695), the first reported deletion causing autosomal dominant AD. Affected individuals have an age at symptom onset in their early forties and suffer from a rapidly progressing disease course. Symptoms and biomarkers are typical of sporadic AD, except that these three patients had high cerebrospinal fluid (CSF) Aβ42 and only modest brain pathology as detected by amyloid-positron emission tomography. Mass spectrometry and Western blot analyses of patient CSF and media from experimental cell cultures indicate that the Uppsala APP mutation alters APP processing by increasing β-secretase cleavage and affecting α-secretase cleavage. Furthermore, in vitro aggregation studies and analyses of patient brain tissue samples indicate that the longer form of mutated Aβ, AβUpp1–42Δ19–24, accelerates the formation of fibrils with unique polymorphs and their deposition into amyloid plaques in the affected brain.

• Edwin, Trine Holt; Henjum, Kristi; Nilsson, Lars; Watne, Leiv; Persson, Karin Ester Torun & Eldholm, Rannveig Sakshaug [Vis alle 12 forfattere av denne artikkelen] (2020). A high cerebrospinal fluid soluble TREM2 level is associated with slow clinical progression of Alzheimer's disease. Alzheimer's & Dementia. ISSN 1552-5260. 12(1). doi: 10.1002/dad2.12128. Fulltekst i vitenarkiv Vis sammendrag

  Introduction: The progression rate of Alzheimer's disease (AD) varies and might be affected by the triggering receptor expressed on myeloid cells (TREM2) activity. We explored if cerebrospinal fluid (CSF) soluble TREM2 (sTREM2), a proxy of microglial activity, is associated with clinical progression rate. Methods: Patients with clinical AD (N = 231) were followed for up to 3 years after diagnosis. Cognitively healthy controls (N = 42) were followed for 5 years. CSF sTREM2 was analyzed by enzyme-linked immunosorbent assay. Group-based trajectory modeling revealed distinct clinical progression groups. Results: Higher CSF sTREM2 was associated with slow clinical progression. The slow- and medium-progressing groups had higher CSF sTREM2 than the cognitively healthy, who had a similar level to patients with rapid clinical progression. Discussion: CSF sTREM2 levels were associated with clinical progression in AD, regardless of core biomarkers. This could be useful in assessing disease development in relation to patient care and clinical trial recruitment. Keywords: Alzheimer's disease; Clinical Dementia Rating scale; disease progression; soluble triggering receptor expressed on myeloid cells 2 (sTREM2); trajectories.

• Henjum, Kristi; Årskog, Vibeke Helen; Jendresen, Charlotte Bille; Fladby, Tormod; Torp, Reidun & Nilsson, Lars (2020). Analyzing microglial-associated Aβ in Alzheimer’s disease transgenic mice with a novel mid-domain Aβ-antibody. Scientific Reports. 10(10590). doi: 10.1038/s41598-020-67419-2. Fulltekst i vitenarkiv Vis sammendrag

  The mechanisms of amyloid-β (Aβ)-degradation and clearance in Alzheimer’s disease (AD) pathogenesis have been relatively little studied. Short Aβ-fragments form by enzymatic cleavage and alternate amyloid-beta precursor protein (APP)-processing. Here we characterized a novel polyclonal Aβ-antibody raised against an Aβ mid-domain and used it to investigate microglial Aβ-uptake in situ by microscopy at the light- and ultrastructural levels. The rabbit Aβ-mid-domain antibody (ab338), raised against the mid-domain amino acids 21–34 (Aβ21–34), was characterized with biochemical and histological techniques. To identify the epitope in Aβ recognized by ab338, solid phase and solution binding data were compared with peptide folding scores as calculated with the Tango software. The ab338 antibody displayed high average affinity (KD: 6.2 × 10−10 M) and showed preference for C-terminal truncated Aβ-peptides ending at amino acid 34 and Aβ-mid domain peptides with high scores of β-turn structure. In transgenic APP-mouse brain, ab338 labelled amyloid plaques and detected Aβ-fragments in microglia at the ultra- and light microscopic levels. This reinforces a role of microglia/macrophages in Aβ-clearance in vivo. The ab338 antibody might be a valuable tool to study Aβ-clearance by microglial uptake and Aβ-mid-domain peptides generated by enzymatic degradation and alternate production.

• Knapskog, Anne Brita; Henjum, Kristi; Idland, Ane-Victoria; Eldholm, Rannveig Sakshaug; Persson, Karin Ester Torun & Saltvedt, Ingvild [Vis alle 9 forfattere av denne artikkelen] (2020). Cerebrospinal fluid sTREM2 in Alzheimer’s disease: comparisons between clinical presentation and AT classification. Scientific Reports. 10, s. 1–10. doi: 10.1038/s41598-020-72878-8. Fulltekst i vitenarkiv Vis sammendrag

  Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed by microglia. Its cleaved fragments, soluble TREM2 (sTREM2), can be measured in the cerebrospinal fluid (CSF). Previous studies indicate higher CSF sTREM2 in symptomatic AD; however most of these studies have included biomarker positive AD cases and biomarker negative controls. The aim of the study was to explore potential differences in the CSF level of sTREM2 and factors associated with an increased sTREM2 level in patients diagnosed with mild cognitive impairment (MCI) or dementia due to AD compared with cognitively unimpaired controls as judged by clinical symptoms and biomarker category (AT). We included 299 memory clinic patients, 62 (20.7%) with AD-MCI and 237 (79.3%) with AD dementia, and 113 cognitively unimpaired controls. CSF measures of the core biomarkers were applied to determine AT status. CSF sTREM2 was analyzed by ELISA. Patients presented with comparable CSF sTREM2 levels as the cognitively unimpaired (9.6 ng/ml [SD 4.7] versus 8.8 ng/ml [SD 3.6], p = 0.27). We found that CSF sTREM2 associated with age-related neuroinflammation and tauopathy irrespectively of amyloid β, APOE ε4 status or gender. The findings were similar in both symptomatic and non-symptomatic individuals.

• Halaas, Nathalie Bodd; Henjum, Kristi; Blennow, Kaj; Dakhil, Shams; Idland, Ane-Victoria & Nilsson, Lars [Vis alle 13 forfattere av denne artikkelen] (2019). CSF sTREM2 and Tau Work Together in Predicting Increased Temporal Lobe Atrophy in Older Adults. Cerebral Cortex. ISSN 1047-3211. 00, s. 1–12. doi: 10.1093/cercor/bhz240. Fulltekst i vitenarkiv Vis sammendrag

  Neuroinflammation may be a key factor in brain atrophy in aging and age-related neurodegenerative disease. The objective of this study was to test the association between microglial expression of soluble Triggering Receptor Expressed on Myeloid Cells 2 (sTREM2), as a measure of neuroinflammation, and brain atrophy in cognitively unimpaired older adults. Brain magnetic resonance imagings (MRIs) and cerebrospinal fluid (CSF) sTREM2, total tau (t-tau), phosphorylated181 tau (p-tau), and Aβ42 were analyzed in 115 cognitively unimpaired older adults, classified according to the A/T/(N)-framework. MRIs were repeated after 2 (n = 95) and 4 (n = 62) years. High baseline sTREM2 was associated with accelerated cortical thinning in the temporal cortex of the left hemisphere, as well as bilateral hippocampal atrophy, independently of age, Aβ42, and tau. sTREM2-related atrophy only marginally increased with biomarker positivity across the AD continuum (A−T− #x2292; A+T− #x2292; A+T+) but was significantly stronger in participants with a high level of p-tau (T+). sTREM2-related cortical thinning correlated significantly with areas of high microglial-specific gene expression in the Allen Human Brain Atlas. In conclusion, increased CSF sTREM2 was associated with accelerated cortical and hippocampal atrophy in cognitively unimpaired older participants, particularly in individuals with tau pathology. This suggests a link between neuroinflammation, neurodegeneration, and amyloid-independent tauopathy.

• Jendresen, Charlotte Bille; Digre, Andreas; Cui, Hao; Zhang, Xiao; Vlodavsky, Israel & Li, Jin-Ping [Vis alle 7 forfattere av denne artikkelen] (2019). Systemic LPS-induced Aβ-solubilization and clearance in AβPP-transgenic mice is diminished by heparanase overexpression. Scientific Reports. 9:4600(1), s. 1–12. doi: 10.1038/s41598-019-40999-4. Fulltekst i vitenarkiv Vis sammendrag

  Amyloid-β (Aβ) is the main constituent of amyloid deposits in Alzheimer’s disease (AD). The neuropathology is associated with neuroinflammation. Here, we investigated effects of systemic lipopolysaccharide (LPS)-treatment on neuroinflammation and Aβ deposition in AβPP-mice and double-transgenic mice with brain expression of AβPP and heparanase, an enzyme that degrades HS and generates an attenuated LPS-response. At 13 months of age, the mice received a single intraperitoneal injection of 50 µg LPS or vehicle, and were sacrificed 1.5 months thereafter. Aβ in the brain was analyzed histologically and biochemically after sequential detergent extraction. Neuroinflammation was assessed by CD45 immunostaining and mesoscale cytokine/chemokine ELISA. In single-transgenic mice, LPS-treatment reduced total Aβ deposition and increased Tween-soluble Aβ. This was associated with a reduced CXCL1, IL-1β, TNF-α-level and microgliosis, which correlated with amyloid deposition and total Aβ. In contrast, LPS did not change Aβ accumulation or inflammation marker in the double-transgenic mice. Our findings suggest that a single pro-inflammatory LPS-stimulus, if given sufficient time to act, triggers Aβ-clearance in AβPP-transgenic mouse brain. The effects depend on HS and heparanase.

• Nordengen, Kaja; Kirsebom, Bjørn-Eivind; Henjum, Kristi; Selnes, Per; Gisladottir, Berglind & Wettergreen, Marianne [Vis alle 12 forfattere av denne artikkelen] (2019). Glial activation and inflammation along the Alzheimer's disease continuum. Journal of Neuroinflammation. 16:46(46), s. 1–13. doi: 10.1186/s12974-019-1399-2. Fulltekst i vitenarkiv Vis sammendrag

  Background Neuronal and glial cell interaction is essential for synaptic homeostasis and may be affected in Alzheimer’s disease (AD). We measured cerebrospinal fluid (CSF) neuronal and glia markers along the AD continuum, to reveal putative protective or harmful stage-dependent patterns of activation. Methods We included healthy controls (n = 36) and Aβ-positive (Aβ+) cases (as defined by pathological CSF amyloid beta 1-42 (Aβ42)) with either subjective cognitive decline (SCD, n = 19), mild cognitive impairment (MCI, n = 39), or AD dementia (n = 27). The following CSF markers were measured: a microglial activation marker—soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a marker of microglial inflammatory reaction—monocyte chemoattractant protein-1 (MCP-1), two astroglial activation markers—chitinase-3-like protein 1 (YKL-40) and clusterin, a neuron-microglia communication marker—fractalkine, and the CSF AD biomarkers (Aβ42, phosphorylated tau (P-tau), total tau (T-tau)). Using ANOVA with planned comparisons, or Kruskal-Wallis tests with Dunn’s pairwise comparisons, CSF levels were compared between clinical groups and between stages of biomarker severity using CSF biomarkers for classification based on amyloid pathology (A), tau pathology (T), and neurodegeneration (N) giving rise to the A/T/N score. Results Compared to healthy controls, sTREM2 was increased in SCD (p < .01), MCI (p < .05), and AD dementia cases (p < .001) and increased in AD dementia compared to MCI cases (p < .05). MCP-1 was increased in MCI (p < .05) and AD dementia compared to both healthy controls (p < .001) and SCD cases (p < .01). YKL-40 was increased in dementia compared to healthy controls (p < .01) and MCI (p < .05). All of the CSF activation markers were increased in subjects with pathological CSF T-tau (A+T−N+ and A+T+N+), compared to subjects without neurodegeneration (A−T−N− and A+T−N−). Discussion Microglial activation as indicated by increased sTREM2 is present already at the preclinical SCD stage; increased MCP-1 and astroglial activation markers (YKL-40 and clusterin) were noted only at the MCI and AD dementia stages, respectively, and in Aβ+ cases (A+) with pathological T-tau (N+). Possible different effects of early and later glial activation need to be explored.

• Henjum, Kristi; Paulsen, Else Quist; Zetterberg, Henrik; Blennow, Kaj; Nilsson, Lars & Watne, Leiv (2018). CSF sTREM2 in delirium - Relation to Alzheimer's disease CSF biomarkers Abeta42, t-tau and p-tau. Journal of Neuroinflammation. 15(1), s. 1–15. doi: 10.1186/s12974-018-1331-1. Fulltekst i vitenarkiv Vis sammendrag

  Background Delirium and dementia share symptoms of cognitive dysfunctions, and mechanisms of neuroinflammation appear involved in both conditions. Triggering receptor expressed on myeloid cells 2 (TREM2) is linked to dementia and neurodegenerative disease. It encodes expression of an innate immune receptor in the brain expressed by microglia. The level of the soluble fragment of TREM2 (sTREM2) is reported to increase in the cerebrospinal fluid (CSF) already in prodromal and asymptomatic Alzheimer’s disease. Methods We analyzed the level of CSF sTREM2 in relation to delirium and dementia. The study included patients with or without pre-existing dementia who underwent acute hip fracture surgery (n = 120), and some of the patients developed delirium (n = 65). A medical delirium cohort (n = 26) was also examined. ELISA was used to determine the level of sTREM2 in CSF. Results Delirium was associated with a higher level of CSF sTREM2 only among those without pre-existing dementia (p = 0.046, n = 15, n = 44), particularly among patients developing delirium after CSF sampling (p = 0.02, n = 7, n = 44). Between patients with dementia, there was no group difference, but the CSF sTREM2 level increased with waiting time for surgery (rS = 0.39, p = 0.002, n = 60) and correlated well with the CSF Alzheimer’s disease biomarkers, Aβ42, and t-tau/p-tau (rS = 0.40, p = 0.002, rS = 0.46, p < 0.001/ rS = 0.49, p < 0.001, n = 60). Among patients with dementia, the level of Aβ38 and Aβ40 also correlated positively with sTREM2 in CSF (Aβ38MSDrS = 0.44, p = 0.001; Aβ40MSDrS = 0.48, p < 0.001; Aβ42MSDrS = 0.43, p < 0.001, n = 60). Conclusion The findings reinforce the involvement of neuroinflammation in delirium, yet with separate responses in patients with or without pre-existing dementia. Our findings support the concept of primed microglia in neurodegenerative disease and central immune activation after a peripheral trauma in such patients. A CSF biomarker panel of neuroinflammation might be valuable to prevent delirium by identifying patients at risk.

• Jendresen, Charlotte Bille; Daws, Michael Rory & Nilsson, Lars (2018). An improved CPRG colorimetric ligand-receptor signal transduction assay based on beta-galactosidase activity in mammalian BWZ-reporter cells. Journal of pharmacological and toxicological methods. ISSN 1056-8719. 90, s. 67–75. doi: 10.1016/j.vascn.2017.11.004. Fulltekst i vitenarkiv Vis sammendrag

  Introduction: Reporter cells expressing a chimeric receptor that activates a reporter can be used for screening ligand-mediated signal transduction. In this study, we used reporter cells harboring an NFAT/lacZ construct that express β-galactosidase when the chimeric receptor is stimulated. A colorimetric β-galactosidase substrate, chlorophenol-red β-d-galactopyranoside (CPRG), was used to detect enzymatic activity. Sub-optimal conditions have unfortunately extensively been reported with such reporter-based β-galactosidase assays. Here, we aimed to improve the CPRG-based colorimetric assay such that receptor ligands could be effectively screened with reporter cells. Methods: After stimulation of reporter cells, we determined β-galactosidase activity by absorbance measurement of β-galactosidase-dependent CPRG hydrolysis. We systematically examined each component in a standard lysis buffer most commonly reported for this type of reporter cells. Furthermore, we evaluated literature in the field. Results: An increased CPRG substrate concentration combined with a different detergent, Saponin, and an optimal wavelength recording markedly increased the sensitivity for the detection of β-galactosidase activity (≈ 4-fold increase). Moreover, the improved protocol resulted in increased linear time-dependent recording of enzymatic activity once cells had been lysed, and a more stable and reproducible assay to detect a ligand-stimulus with the reporter cells. The optimal time length of exposure to a stimulus was ligand-dependent. Discussion: In conclusion, we provide an improved protocol with an optimized lysis buffer that gives up to a six-fold higher and more robust specific signal when NFAT/lacZ-based receptor-expressing reporter cells are exposed to a stimulus.

• Jendresen, Charlotte Bille; Årskog, Vibeke Helen; Daws, Michael Rory & Nilsson, Lars (2017). The Alzheimer's disease risk factors apolipoprotein E and TREM2 are linked in a receptor signaling pathway. Journal of Neuroinflammation. 14:59, s. 1–13. doi: 10.1186/s12974-017-0835-4. Fulltekst i vitenarkiv Vis sammendrag

  Background Triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (APOE) are genetically linked to Alzheimer’s disease. Here, we investigated whether human ApoE mediates signal transduction through human and murine TREM2 and sought to identify a TREM2-binding domain in human ApoE. Methods To investigate cell signaling through TREM2, a cell line was used which expressed an NFAT-inducible β-galactosidase reporter and human or murine TREM2, fused to CD8 transmembrane and CD3ζ intracellular signaling domains. ELISA-based binding assays were used to determine binding affinities of human ApoE isoforms to human TREM2 and to identify a TREM2-binding domain in ApoE. Results ApoE was found to be an agonist to human TREM2 with EC50 in the low nM range, and to murine TREM2 with reduced potency. In the reporter cells, TREM2 expression was lower than in nontransgenic mouse brain. Human ApoE isoforms ε2, ε3, and ε4 bound to human TREM2 with K d in the low nM range. The binding was displaced by an ApoE-mimetic peptide (amino acids 130–149). Conclusions An ApoE-mediated dose-dependent signal transduction through TREM2 in reporter cells was demonstrated, and a TREM2-binding region in ApoE was identified. The relevance of an ApoE-TREM2 receptor signaling pathway to Alzheimer’s disease is discussed.

• Henjum, Kristi; Almdahl, Ina; Årskog, Vibeke Helen; Minthon, Lennart; Hansson, Oskar & Fladby, Tormod [Vis alle 7 forfattere av denne artikkelen] (2016). Cerebrospinal fluid soluble TREM2 in aging and Alzheimer's disease. Alzheimer's Research & Therapy. 8(1). doi: 10.1186/s13195-016-0182-1. Fulltekst i vitenarkiv Vis sammendrag

  Background Alzheimer’s disease (AD) neuropathology is associated with neuroinflammation, but there are few useful biomarkers. Mutant variants of triggering receptor expressed on myeloid cells 2 (TREM2) have recently been linked to late-onset AD and other neurodegenerative disorders. TREM2, a microglial receptor, is involved in innate immunity. A cleaved fragment, soluble TREM2 (sTREM2), is present in the cerebrospinal fluid (CSF). Methods We developed and used a novel enzyme-linked immunosorbent assay to investigate the potential value of CSF sTREM2 as an AD biomarker in two independent cohorts: an AD/mild cognitive impairment (MCI)/control cohort (n = 100) and an AD/control cohort (n = 50). Results We found no significant difference in sTREM2 levels between groups of controls and patients with AD or MCI. However, among all controls there was a positive correlation between sTREM2 and age (Spearman rho = 0.50; p < 0.001; n = 75). In the AD/MCI/control cohort, CSF sTREM2 correlated positively with total Tau (T-tau) (Spearman rho 0.57; p < 0.001; n = 50), phosphorylated Tau (P-tau) (Spearman rho 0.63; p < 0.001; n = 50) and amyloid-β1–42 (Aβ42) (Spearman rho 0.35; p = 0.01; n = 50) in control subjects. Among controls with a CSF Aβ42 above a cut-off value (700 pg/ml) in this cohort, the positive correlation between sTREM2 and Aβ42 was stronger (Spearman rho = 0.44; p = 0.002; n = 46). Conclusions sTREM2 in CSF correlates with aging in controls, and with the neurodegenerative markers CSF T-tau/P-tau among controls who are negative for AD CSF core biomarkers Aβ42, T-tau or P-tau.

• Nordeman, Patrik; Johansson, Leif B.G.; Bäck, Marcus; Estrada, Sergio; Hall, Håkan & Sjölander, Daniel [Vis alle 12 forfattere av denne artikkelen] (2016). 11C and 18F-Radiolabeling of Tetra- and Pentathiophenes as PET-Ligands for Amyloid Protein Aggregates. ACS Medicinal Chemistry Letters. 7(4), s. 368–373. doi: 10.1021/acsmedchemlett.5b00309. Fulltekst i vitenarkiv
• Jendresen, Charlotte Bille; Cui, Hao; Zhang, Xiao; Vlodavsky, Israel; Nilsson, Lars & Li, Jin-Ping (2015). Overexpression of heparanase lowers the amyloid burden in amyloid-β precursor Protein Transgenic mice. Journal of Biological Chemistry. ISSN 0021-9258. 290(8), s. 5053–5064. doi: 10.1074/jbc.M114.600569. Fulltekst i vitenarkiv
• Røgeberg, Magnus; Wettergreen, Marianne; Nilsson, Lars & Fladby, Tormod (2015). Identification of amyloid beta mid-domain fragments in human cerebrospinal fluid. Biochimie. ISSN 0300-9084. 113, s. 86–92. doi: 10.1016/j.biochi.2015.03.022. Fulltekst i vitenarkiv
• Røgeberg, Magnus; Almdahl, Ina; Wettergreen, Marianne; Nilsson, Lars & Fladby, Tormod (2015). Isobaric Quantification of Cerebrospinal Fluid Amyloid-β Peptides in Alzheimer's Disease: C-Terminal Truncation Relates to Early Measures of Neurodegeneration. Journal of Proteome Research. ISSN 1535-3893. 14(11), s. 4834–4843. doi: 10.1021/acs.jproteome.5b00668. Fulltekst i vitenarkiv
• Nuruddin, Syed; Syverstad, Gry-Helen Enger; Lillehaug, Sveinung; Leergaard, Trygve Brauns; Nilsson, Lars & Ropstad, Erik [Vis alle 9 forfattere av denne artikkelen] (2014). Elevated mRNA-Levels of Gonadotropin-Releasing Hormone and Its Receptor in Plaque-Bearing Alzheimer's Disease Transgenic Mice. PLOS ONE. 9(8). doi: 10.1371/journal.pone.0103607. Fulltekst i vitenarkiv
• Lillehaug, Sveinung; Syverstad, Gry-Helen Enger; Nilsson, Lars; Bjaalie, Jan G.; Leergaard, Trygve Brauns & Torp, Reidun (2014). Brainwide distribution and variance of amyloid-beta deposits in tg-ArcSwe mice. Neurobiology of Aging. ISSN 0197-4580. 35(3), s. 556–564. doi: 10.1016/j.neurobiolaging.2013.09.013. Fulltekst i vitenarkiv
• Lillenes, Meryl Sønderby; Støen, Mari; Gómez-Muñoz, Marta; Torp, Reidun; Günther, Clara-Cecilie & Nilsson, Lars [Vis alle 7 forfattere av denne artikkelen] (2013). Transient OGG1, APE1, PARP1 and Polβ expression in an Alzheimer's disease mouse model. Mechanisms of Ageing and Development. ISSN 0047-6374. 134(10), s. 467–477. doi: 10.1016/j.mad.2013.09.002. Fulltekst i vitenarkiv Vis sammendrag

  Alzheimer's disease (AD) is a disease of major public health significance, whose pathogenesis is strongly linked to the presence of fibrillar aggregates of amyloid-beta (Aβ) in the aging human brain. We exploited the transgenic (Tg)-ArcSwe mouse model for human AD to explore whether oxidative stress and the capacity to repair oxidative DNA damage via base excision repair (BER) are related to Aβ pathology in AD. Tg-ArcSwe mice express variants of Aβ, accumulating senile plaques at 4–6 months of age, and develop AD-like neuropathology as adult animals. The relative mRNA levels of genes encoding BER enzymes, including 8-oxoguanine glycosylase (OGG1), AP endonuclease 1 (APE1), polymerase β (Polβ) and poly(ADP-ribose) polymerase 1 (PARP1), were quantified in various brain regions of 6 weeks, 4 months and 12 months old mice. The results show that OGG1 transcriptional expression was higher, and APE1 expression lower, in 4 months old Tg-ArcSwe than in wildtype (wt) mice. Furthermore, Polβ transcriptional expression was significantly lower in transgenic 12 months old mice than in wt. Transcriptional profiling also showed that BER repair capacity vary during the lifespan in Tg-ArcSwe and wt mice. The BER expression pattern in Tg-ArcSwe mice thus reflects responses to oxidative stress in vulnerable brain structures.

• Magnusson, Kristina; Sehlin, Dag; Syvänen, Stina; Svedberg, Marie M.; Philipson, Ola & Söderberg, Linda [Vis alle 14 forfattere av denne artikkelen] (2013). Specific Uptake of an Amyloid-beta Protofibril-Binding Antibody-Tracer in A beta PP Transgenic Mouse Brain. Journal of Alzheimer's Disease. ISSN 1387-2877. 37(1), s. 29–40. doi: 10.3233/JAD-130029. Fulltekst i vitenarkiv
• Gumucio, Astrid; Lannfelt, Lars & Nilsson, Lars (2013). Lack of exon 10 in the murine tau gene results in mild sensorimotor defects with aging. BMC Neuroscience. 14:148. doi: 10.1186/1471-2202-14-148. Fulltekst i vitenarkiv Vis sammendrag

  Background Complex species-specific, developmental- and tissue-dependent mechanisms regulate alternative splicing of tau, thereby diversifying tau protein synthesis. The functional role of alternative splicing of tau e.g. exon 10 has never been examined in vivo, although genetic studies suggest that it is important to neurodegenerative disease. Results Gene-targeting was used to delete exon 10 in murine tau on both alleles (E10−/−) to study its functional role. Moreover, mice devoid of exon 10 (E10+/−) on one allele were generated to investigate the effects of 1:1 balanced expression of 4R-/3R-tau protein, since equal amounts of 4R-/3R-tau protein are synthesized in human brain. Middle-aged E10−/− mice displayed sensorimotor disturbances in the rotarod when compared to age-matched E10+/− and wild-type mice, and their muscular grip strength was less than that of E10+/− mice. The performance of E10+/− mice and wild-type mice (E10+/+) was similar in sensorimotor tests. Cognitive abilities or anxiety-like behaviours did not depend on exon 10 in tau, and neither pathological inclusions nor gene-dependent morphological abnormalities were found. Conclusion Ablation of exon 10 in the murine tau gene alters alternative splicing and tau protein synthesis which results in mild sensorimotor phenotypes with aging. Presumably related microtubule-stabilizing genes rescue other functions.

• Kalimo, Hannu; Lalowski, Maciej; Bogdanovic, Nenad; Philipson, Ola; Bird, Thomas D. & Nochlin, David [Vis alle 17 forfattere av denne artikkelen] (2013). The Arctic AβPP mutation leads to Alzheimer's disease pathology with highly variable topographic deposition of differentially truncated Aβ. Acta neuropathologica communications. 2(1). doi: 10.1186/2051-5960-1-60. Fulltekst i vitenarkiv
• Philipson, O; Lord, A; Lalowski, M; Soliymani, R; Baumann, M & Thyberg, J [Vis alle 13 forfattere av denne artikkelen] (2012). The Arctic amyloid-beta precursor protein (A beta PP) mutation results in distinct plaques and accumulation of N- and C-truncated A beta. Neurobiology of Aging. ISSN 0197-4580. 33(5). doi: 10.1016/j.neurobiolaging.2011.10.022. Fulltekst i vitenarkiv

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