Endogenous Aβ causes cell death via early tau hyperphosphorylation

Alzheimer's disease (AD) is characterized by A beta 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 A beta antibodies or by specific beta and/or gamma-secretases inhibitors; (ii) temporally precedes tau cleavage mediated by a delayed (6-12 h after NGF withdrawal) activation of caspase-3 and calpain-I; (iii) under control of Akt-GSK3 beta-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 A beta 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. (C) 2009 Elsevier Inc. All rights reserved.