Possible role of tau phosphorylation on ER membrane in Alzheimer pathology

Abstract

The pathology of Alzheimer’s disease (AD) is characterized by intracellular neurofibrillary tangles (NFTs), extracellular senile plaques (SPs), neuronal loss and a chronic inflammatory state. The number of NFTs correlates directly with the severity of dementia [1]. NFTs are composed of straight or paired helical filaments (PHFs) with a major component being an aberrantly hyperphosphorylated form of the microtubule-associated protein (MAP) tau [2]. Such abnormal filaments accumulate in the cell bodies of degenerating neurons, as well as in the neuropil threads and dystrophic neurites in SPs. In the normal brain, tau promotes the assembly and stabilization of microtubules [3]. The ability of tau to bind to microtubules is, however, down-regulated after phosphorylation, especially after local phosphorylation in the C-terminal repeats of the microtubule-binding domain [4, 5]. Tau can be phosphorylated at multiple sites by many kinases. Although abnormal tau aggregation into PHFs has long been attributed to abnormal phosphorylation of tau [2], fetal and biopsy-derived tau proteins were found to be phosphorylated at almost the same sites as PHF-tau [6]. Therefore, dysfunctions of protein phosphatases such as calcineurin or PP2A were recently postulated in AD brain tissues.