Abeta oligomers cause local missorting of endogenous tau into dendrites, tau phosphorylation, destruction of microtubules and spines

Abstract

Abnormal changes and aggregation of amyloid-beta (Abeta) and Tau protein are two hallmarks of Alzheimer's Disease (AD), and according to the Abeta-cascade hypothesis, Abeta is considered toxic for neurons and Tau a downstream target of Abeta. We have investigated primary hippocampal neurons for early and subtle changes following exposure to Abeta oligomers. Initial events become evident by missorting of endogenous Tau into the soma and dendrites, in contrast to their axonal sorting in normal neurons. In the missorted dendritic regions there is a depletion of spines and spine-related proteins. Tau in these regions shows elevated phosphorylation at several sites that are diagnostic of AD-Tau (notably at the 12E8 epitope, pS262/pS356, and the AT8 epitope, pS202/pT205), and local elevation of relevant kinase activity (e.g. microtubule affinity regulating kinase (MARK)). These local effects occur without major global changes in Tau, tubulin, kinase levels or activities. Missorting affects not only Tau, but also other axonal markers such as neurofilaments, and correlates with a local decrease of microtubules. Similar early changes can be evoked by other cell stressors. We conclude that Abeta oligomers evoke responses that disrupt the axonal sorting machinery, allow endogenous Tau to enter dendrites and to destroy spines and microtubules locally. This is in analogy to the loss of spines and microtubules observed in AD.