Calcium-mediated Transient Phosphorylation of Tau and Amyloid Precursor Protein Followed by Intraneuronal Amyloid-β Accumulation

Susana Ferrao Santos,Jean-Noël Octave,Nathalie Pierrot,Jean-Pierre Brion,Christine Feyt,Marina Morel

doi:10.1074/jbc.m606015200

Abstract

Intraneuronal accumulation of hyperphosphorylated protein tau in paired helical filaments together with amyloid-beta peptide (Abeta) deposits confirm the clinical diagnosis of Alzheimer disease. A common cellular mechanism leading to the production of these potent toxins remains elusive. Here we show that, in cultured neurons, membrane depolarization induced a calcium-mediated transient phosphorylation of both microtubule-associated protein tau and amyloid precursor protein (APP), followed by a dephosphorylation of these proteins. Phosphorylation was mediated by glycogen synthase kinase 3 and cyclin-dependent kinase 5 protein kinases, while calcineurin was responsible for dephosphorylation. Following the transient phosphorylation of APP, intraneuronal Abeta accumulated and induced neurotoxicity. Phosphorylation of APP on Thr-668 was indispensable for intraneuronal accumulation of Abeta. Our data demonstrate that an increase in cytosolic calcium concentration induces modifications of neuronal metabolism of APP and tau, similar to those found in Alzheimer disease.

Highlights

In 1985, the major constituents of senile plaques and neurofibrillary tangles, which coexist in Alzheimer disease (AD), were identified as A␤ and tau, respectively [2, 4]
Investigators studying the metabolism of tau have provided strong evidence that hyperphosphorylated protein tau plays a key role in the development of AD
Strong evidence that A␤ is the causative agent of AD was provided by the study of familial cases in which gene mutations give rise to an increased production of A␤ [6]

Summary

Introduction

We show that in cultured neurons membrane depolarization induced a calcium-mediated transient phosphorylation of APP and tau by the Cdk5 and GSK3 protein kinases, followed by a dephosphorylation of both proteins. This intraneuronal accumulation of A␤1– 42 was not observed following expression of the APPT668A mutant, indicating that phosphorylation of APP on Thr-668 was indispensable. Neurons were depolarized during 10 min before reincubation for different times up to 7 h in a culture medium without KCl. Depolarization did not induce any modification of APP or tau expression.

Results

Conclusion