Pradhan, Arpit Kumar and Neumueller, Tatjana and Klug, Claudia and Fuchs, Severin and Schlegel, Martin and Ballmann, Markus and Tartler, Katharina Johanna and Pianos, Antoine and Garcia, Maria Sanchez and Liere, Philippe and Schumacher, Michael and Kreuzer, Matthias and Rupprecht, Rainer and Rammes, Gerhard (2023) Chronic administration of XBD173 ameliorates cognitive deficits and neuropathology via 18 kDa translocator protein (TSPO) in a mouse model of Alzheimer's disease. TRANSLATIONAL PSYCHIATRY, 13 (1): 332. ISSN 2158-3188,
Full text not available from this repository. (Request a copy)Abstract
Alzheimer's disease (AD) is characterized by the accumulation of beta-amyloid peptide (A beta). It affects cognition and leads to memory impairment. The mitochondrial translocator protein (TSPO) plays an essential role in maintaining mitochondrial homeostasis and has been implicated in several neuronal disorders or neuronal injuries. Ligands targeting the mitochondrial translocator protein (18 kDa), promote neurosteroidogenesis and may be neuroprotective. To study whether the TSPO ligand XBD173 may exert early neuroprotective effects in AD pathology we investigated the impact of XBD173 on amyloid toxicity and neuroplasticity in mouse models of AD. We show that XBD173 (emapunil), via neurosteroid-mediated signaling and delta subunit-containing GABAA receptors, prevents the neurotoxic effect of A beta on long-term potentiation (CA1-LTP) in the hippocampus and prevents the loss of spines. Chronic but not acute administration of XBD173 ameliorates spatial learning deficits in transgenic AD mice with arctic mutation (ArcA beta). The heterozygous TSPO-knockout crossed with the transgenic arctic mutation model of AD mice (het TSPOKO X ArcA beta) treated with XBD173 does not show this improvement in spatial learning suggesting TSPO is needed for procognitive effects of XBD173. The neuroprotective profile of XBD173 in AD pathology is further supported by a reduction in plaques and soluble A beta levels in the cortex, increased synthesis of neurosteroids, rescued spine density, reduction of complement protein C1q deposits, and reduced astrocytic phagocytosis of functional synapses both in the hippocampus and cortex. Our findings suggest that XBD173 may exert therapeutic effects via TSPO in a mouse model of AD.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | LONG-TERM POTENTIATION; A-BETA; AMYLOID-BETA; COMPLEMENT; RECEPTOR; LIGAND; MICROGLIA; ACTIVATION; INHIBITION; MEMORY; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Psychiatrie und Psychotherapie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 23 Mar 2024 09:54 |
| Last Modified: | 23 Mar 2024 09:54 |
| URI: | https://pred.uni-regensburg.de/id/eprint/60425 |
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