Tau pathology as a target in Alzheimer's therapeutics

Abstract

Alzheimer disease (AD) and related tauopathies are all characterized histopathologically by neurofibrillary degeneration of abnormally hyperphosphorylated tau. Unlike normal tau which promotes assembly and maintains structure of microtubules, the abnormal tau sequesters normal tau, MAP1, and MAP2, and causes disassembly of microtubules. This toxic behavior of the abnormal tau is solely due to its hyperphosphorylation because dephosphorylation restores it into a normal-like protein. The abnormal hyperphosphorylation also promotes the self-assembly of tau into paired helical filaments (PHF)/straight filaments (SF) but, unlike the soluble abnormally hyperphosphorylated tau, the fibrillized protein is inert and it neither promotes nor inhibits microtubule assembly. The state of phosphorylation of a phosphoprotein is the function of the activities of protein kinases and as well as of protein phosphatases that regulate the level of phosphorylation. A cause of the abnormal hyperphosphorylation in AD brain is a decrease in the activity of protein phosphatase (PP)-2A, a major regulator of the phosphorylation of tau. A decrease in PP-2A activity results in the abnormal hyperphosphorylation of tau not only by decreased dephosphorylation of tau but also by stimulating the activities of tau kinases like CaMKII, PKA, and MAP, which are regulated by PP-2A. Thus, the abnormal hyperphosphorylation can be inhibited both by inhibition of the activity of a tau protein kinase and by restoration of the activity of PP-2A. The development of drugs that inhibit neurofibrillary degeneration of abnormally hyperphosphorylated tau is a very promising and feasible therapeutic approach to inhibit the progression of AD and related tauopathies.