Anna Maria Gorska

• 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.

• 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.

• Hernandez, Cristian; Gorska, Anna Maria & Eugenin, Eliseo (2024). Mechanisms of HIV-mediated blood-brain barrier compromise and leukocyte transmigration under the current antiretroviral era. iScience. 27(3), s. 1–24. doi: 10.1016/j.isci.2024.109236. Fulltekst i vitenarkiv Vis sammendrag

  HIV-associated neurological compromise is observed in more than half of all people with HIV (PWH), even under antiretroviral therapy (ART). The mechanism has been associated with the early transmigration of HIV-infected monocytes across the BBB in a CCL2 and HIV replication-dependent manner. However, the mechanisms of chronic brain damage are unknown. We demonstrate that all PWH under ART have elevated circulating ATP levels that correlate with the onset of cognitive impairment even in the absence of a circulating virus. Serum ATP levels found in PWH with the most severe neurocognitive impairment trigger the transcellular migration of HIV-infected leukocytes across the BBB in a JAM-A and LFA-1-dependent manner. We propose that targeting transcellular leukocyte transmigration could reduce or prevent the devastating consequences of HIV within the brains of PWH under ART.

• 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.

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