Endogenous Abeta causes cell death via early tau hyperphosphorylation.

Alzheimer's disease (AD) is characterized by Abeta overproduction and tau hyperphosphorylation. We report that an early, transient and site-specific AD-like tau hyperphosphorylation at Ser262 and Thr231 epitopes is temporally and causally related with an activation of the endogenous amyloidogenic pathway that we previously reported in hippocampal neurons undergoing cell death upon NGF withdrawal [Matrone, C., Ciotti, M.T., Mercanti, D., Marolda, R., Calissano, P., 2008b. NGF and BDNF signaling control amyloidogenic route and Ab production in hippocampal neurons. Proc. Natl. Acad. Sci. 105, 13138-13143]. Such tau hyperphosphorylation, as well as apoptotic death, is (i) blocked by 4G8 and 6E10 Abeta antibodies or by specific beta and/or gamma-secretases inhibitors; (ii) temporally precedes tau cleavage mediated by a delayed (6-12h after NGF withdrawal) activation of caspase-3 and calpain-I; (iii) under control of Akt-GSK3beta-mediated signaling. Finally, we show that such site-specific tau hyperphosphorylation causes tau detachment from microtubules and an impairment of mitochondrial trafficking. These results depict, for the first time, a rapid interplay between endogenous Abeta and tau post-translational modifications which act co-ordinately to compromise neuronal functions in the same neuronal system, under physiological conditions as seen in AD brain.