expression of hyperphosphorylated tau in brains of a tauopathy mouse model and the human brain
01/29/2020
Barbara Sárkány1, 1, Katja Hartwich1, Cecília Paraczky2, Panna Hegedüs2, Tugrul Ozdemir1, David Bannerman3, Balázs Hangya2, Zsófia Maglóczky2, Péter Somogyi1, Tim Viney1
1 Department of Pharmacology, University of Oxford, Oxford, UK. 2Institute of Experimental Medicine, Budapest, Hungary. 3Department of Experimental Psychology, University of Oxford, Oxford, UK.
Tau is a major microtubule-associated protein in neurons and promotes microtubule assembly and stability. Neurodegenerative diseases such as Alzheimer's disease and frontotemporal dementia are associated with abnormal hyperphosphorylated tau (p-tau) aggregates. Spread of p-tau may disrupt coordination of neural activity leading to memory impairments. Rhythmic subcortical inputs to the hippocampus, e.g. from the medial septum, are required for coordination of cortical activity underlying spatial memory. In this study, our aim is to test the effects of pathological tau on memory and on neuronal activity in affected brain regions in a mouse model of tauopathy, the THY-Tau22 line, to make predictions about how potential alterations may affect neuronal activity in humans with tauopathy. We also investigated the distribution of p-tau in post-mortem human brain tissue from dementia patients and in similar brain regions in the tauopathy mouse model and identified vulnerable cell types with different molecular markers using immunohistochemistry. We found that p-tau was enriched in distinct brain regions in both mouse and human, and was localised to distinct kinds of neurons and glia. Despite age-related accumulation of p-tau in the mouse model, we did not observe a decline in spatial working memory. In another test, we have confirmed a previous report that the tauopathy model mice preferred remaining in the open arms of an elevated plus maze, suggestive of its involvement in anxiety-related behaviour. Recording and labelling single p-tau-expressing neurons in vivo may reveal the effects of p-tau on firing patterns, which are potential biomarkers for the pathology.