Rescue of synaptosomal glutamate release defects in tau transgenic mice by the tau aggregation inhibitor hydromethylthionine

• Published in: Cellular signalling 2024-09, Vol.121, p.111269, Article 111269
• Main Authors: Cranston, Anna L., Kraev, Igor, Stewart, Mike G., Horsley, David, Santos, Renato X., Robinson, Lianne, Dreesen, Eline, Armstrong, Paul, Palliyil, Soumya, Harrington, Charles R., Wischik, Claude M., Riedel, Gernot
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease, glutamate; Animals; Calcium - metabolism; Disease Models, Animal; Frontotemporal Dementia - genetics; Frontotemporal Dementia - metabolism; Frontotemporal lobar degeneration; Glutamic Acid - metabolism; Humans; Hydromethylthionine; Methylene Blue - analogs & derivatives; Mice; Mice, Transgenic; Synaptosomes; Synaptosomes - metabolism; tau Proteins - metabolism; Tauopathies - drug therapy; Tauopathies - metabolism
• ISSN: 0898-6568; 1873-3913; 1873-3913
• DOI: 10.1016/j.cellsig.2024.111269

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. •Tau protein aggregation is an underlying feature of multiple forms of dementia.•These tauopathies were modelled in two mouse models.•Glutamate release from neuro-synaptosomes was abnormal in Tau transgenic models.•HMTM, a Tau aggregation inhibitor fully reversed this condition in both models.•Treatment appeared to mitigate imbalances in the calcium homeostasis of the pre-synapses.