Cranston, A.L., Kraev, I., Stewart, M.G. et al. (8 more authors) (2024) Rescue of synaptosomal glutamate release defects in tau transgenic mice by the tau aggregation inhibitor hydromethylthionine. Cellular Signalling, 121. 111269. ISSN 0898-6568
Abstract
Glutamatergic neurotransmission, important for learning and memory, is disrupted in different ways in patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD) tauopathies. We have previously reported that two tau transgenic mouse models, L1 and L66, produce different phenotypes resembling AD and FTD, respectively. The AD-like L1 model expresses the truncated core aggregation domain of the AD paired helical filament (PHF) form of tau (tau296–390) whereas the FTD-like L66 model expresses full-length tau carrying two mutations at P301S/G335D. We have used synaptosomes isolated from these mice to investigate K+-evoked glutamate release and, if abnormal, to determine responsiveness to hydromethylthionine, a tau aggregation inhibitor previously shown to reduce tau pathology in these models. We report that the transgenes in these two mouse lines cause opposite abnormalities in glutamate release. Over-expression of the core tau unit in L1 produces a significant reduction in glutamate release and a loss of Ca²⁺-dependency compared with wild-type control mice. Full-length mutant tau produces an increase in glutamate release that retains normal Ca²⁺-dependency. Chronic pre-treatment with hydromethylthionine normalises both reduced (L1) and excessive glutamate (L66) and restores normal Ca²⁺dependency in L1 mice. This implies that both patterns of impairment are the result of tau aggregation, but that the direction and Ca²⁺-dependency of the abnormality is determined by expression of the disease-specific transgene. Our results lead to the conclusion that the tauopathies need not be considered a single entity in terms of the downstream effects of pathological aggregation of tau protein. In this case, directionally opposite abnormalities in glutamate release resulting from different types of tau aggregation in the two mouse models can be corrected by hydromethylthionine. This may help to explain the activity of hydromethylthionine on cognitive decline and brain atrophy in both AD and behavioural-variant FTD.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | Crown Copyright © 2024 Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
Keywords: | Alzheimer's disease, glutamate; Frontotemporal lobar degeneration; Synaptosomes; Hydromethylthionine |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Psychology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 15 Jul 2024 14:47 |
Last Modified: | 15 Jul 2024 14:47 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.cellsig.2024.111269 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:214267 |