P4-004: abnormal processing and misfolding of tau is modulated by endogenous tau and mutant app/ps1 but not by endogenous app in tau transgenic mice

Expression of mutant tau leads to the formation of fibrillar aggregates in animal models of Alzheimer's disease and other human tauopathies, but it is not completely deciphered to which extent the abnormal misfolding of tau in these aggregates fully reproduce the post-translational modifications of tau observed in human tauopathies, an essential validation step for these models. We have investigated the role of changed expression levels of some genes for their ability to modify the abnormal processing of tau to generate models closer to human tauopathies. Transgenic mice expressing an FTD mutant tau (Tg30 mice) in absence of endogenous wild-type tau, of endogenous APP or in presence of FAD mutant APP and PS1, have been analyzed for their behavioral deficits and the extent of tau aggregation and tau misprocessing. Tg30 mice invalidated for their endogenous tau gene had increased motor impairment, higher levels of phosphorylated and insoluble tau and increased density of NFT in the brain despite lower levels of total tau. 5xFAD x Tg30 mice exhibited a severe increase in motor deficiency and a dramatically increased load in NFT. Insoluble tau in 5xFAD x Tg30 mice compared to insoluble tau in Tg30 mice showed increased phosphorylation, enhanced misfolding and a higher recruitment of endogenous wild-type mouse tau. Inactivation of the APP gene did not change significantly tau pathology in APP-/- x Tg30 mice. Despite these changes in tau misprocessing, some forms of oligomeric tau were not detected in these mice models. These results suggest that increased abnormal misfolding of tau in these animal models is modulated by relative ratios of mutant tau versus non-mutant tau and by expression of mutant APP or PS1, that act as tau-modifiers genes, but is not dependent of expression of endogenous APP. Tg30xtau -/- and 5xFAD x Tg30 mice thus mimics more faithfully, but not completely, tau pathology observed in human tauopathies.