B vitamin deficiency promotes tau phosphorylation through regulation of GSK3beta and PP2A.

Abstract

Neurofibrillary tangles (NFTs), composed of intracellular filamentous aggregates of hyperphosphorylated protein tau, are one of the pathological hallmarks of Alzheimer's disease (AD). Tau phosphorylation is regulated by the equilibrium between activities of its protein kinases and phosphatases; unbalance of these activities is proposed to be a reasonable causative factor to the disease process. Glycogen synthase kinase 3beta (GSK3beta) is one of the most important protein kinase in regulating tau phosphorylation; overexpression of active GSK3beta causes ADlike hyperphosphorylation of tau. Protein phosphatase 2A (PP2A) is the major phosphatase that dephosphorylates tau; it was demonstrated that highly conserved carboxyl-terminal sequence of PP2A C-subunit is a focal point for phosphatase regulation. This is the site of a reversible methyl esterification reaction that controls AB<formula>_{alpha}</formula>C heterotrimers formation. Here we demonstrate that GSK3beta and PP2A genes were upregulated by inhibiting methylation reactions through B vitamin deficiency. In this condition, methylated catalytic subunit PP2Ac was decreased, leading to reduced PP2A activity. By contrast, we observed GSK3beta protein increase and a modulation in phosphorylation sites that regulate GSK3beta activity. Therefore, one-carbon metabolism alteration seems to be a cause of deregulation of the equilibrium between GSK3beta and PP2A, leading to abnormal hyperphosphorylated tau.

DOI: 10.3233/JAD-2010-1284
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@article{Nicolia2010BVD, title={B vitamin deficiency promotes tau phosphorylation through regulation of GSK3beta and PP2A.}, author={Vincenzina Nicolia and Andrea Fuso and Rosaria Adele Cavallaro and Andrea Di Luzio and Sigfrido Scarpa}, journal={Journal of Alzheimer's disease : JAD}, year={2010}, volume={19 3}, pages={895-907} }