Mehul Gajwani, Australia
Macquarie University, Dementia Research Centre Biomedical SciencesAuthor Of 1 Presentation
THE ONSET OF HIPPOCAMPAL NETWORK CHANGES AND MEMORY DECLINE IS ASSOCIATED WITH AN IMMEDIATE EARLY GENE SIGNATURE IN P301S TAU TRANSGENIC MICE
Abstract
Aims
Tau hyperphosphorylation and deposition within the brain is a hallmark feature of several neurodegenerative diseases, including frontotemporal dementia (FTD) and Alzheimer’s disease (AD). Furthermore, tau - but not Aβ pathology - correlates with neurodegeneration and cognitive decline in these diseases. However, how tau pathology drives cellular and molecular mechanisms in cognitive decline is not well understood.
Methods
Therefore, this study aims to investigate the effects of transgenic P301S mutant human tau expression on neuronal network function in the murine hippocampus utilizing the TAU58/2 tau transgenic mouse model. These mice express human P301S mutant tau and recapitulate essential features of AD and FTD, including tau pathology, early-onset disinhibition, and moderate motor deficits.
Results
Here, we found that the onset of spatial memory decline in TAU58/2 transgenic mice was accompanied by an impairment in long-term potentiation (LTP) and neuronal network aberrations during electrophysiological and electroencephalography (EEG) recordings. Further, gene-expression profiling at the onset of deficits in TAU58/2 mice revealed an immediate early gene (IEG) signature that is consistent with neuronal network hypersynchronicity. Finally, we determined that increased IEG activity was confined to neurons harbouring tau pathology, providing a cellular link between abnormal tau and neuronal network dysfunction.
Conclusions
Taken together, our data suggests that tau pathology drives neuronal network dysfunction by hyperexcitation of individual, pathology-harbouring neurons and is a major contributor to memory deficits. Furthermore, this study provides new insights into the pathomechanistic role of tau in disease and may thereby allow the identification of new targets for future translations into therapy.