Abstract
Phosphorylation is one of the most prevalent post-translational modifications found in aggregated tau isolated from Alzheimer’s disease (AD) patient brains. In tauopathies like AD, increased phosphorylation or hyperphosphorylation can contribute to microtubule dysfunction and is associated with tau aggregation. In this review, we provide an overview of the structure and functions of tau protein as well as the physiologic roles of tau phosphorylation. We also extensively survey tau phosphorylation sites identified in brain tissue and cerebrospinal fluid from AD patients compared to age-matched healthy controls, which may serve as disease-specific biomarkers. Recently, new assays have been developed to measure minute amounts of specific forms of phosphorylated tau in both cerebrospinal fluid and plasma, which could potentially be useful for aiding clinical diagnosis and monitoring disease progression. Additionally, multiple therapies targeting phosphorylated tau are in various stages of clinical trials including kinase inhibitors, phosphatase activators, and tau immunotherapy. With promising early results, therapies that target phosphorylated tau could be useful at slowing tau hyperphosphorylation and aggregation in AD and other tauopathies.
Highlights
Overview of tau structure and function Tau protein is encoded in the microtubule associated protein tau (MAPT) gene on chromosome 17
Tau aggregates isolated from Alzheimer’s disease (AD) brains are hyperphosphorylated at multiple residues (Fig. 1 and Table 1)
Tau hyperphosphorylation can lead to MT dysfunction, mislocalization, and increased propensity for aggregation
Summary
Overview of tau structure and function Tau protein is encoded in the microtubule associated protein tau (MAPT) gene on chromosome 17. In early studies, aggregated tau isolated from AD brains was found to have 3–4 fold higher overall phosphorylation levels (8 mol per protein) compared to healthy controls (2–3 mol per protein) [61] This increase in tau phosphorylation within pathological inclusions allows for their detection with tau phosphorylation-specific antibodies (Fig. 2). Effects of tau hyperphosphorylation on microtubule interactions, aggregation and prion-like spread In pathologic states like AD, hyperphosphorylated tau exhibits impaired MT binding and is less capable of promoting MT assembly contributing to a breakdown of MT in late stages of AD [70]. Another consequence of decreased MT binding is the mislocalization of tau from the axon to the cytosol. These include subtypes of Frontotemporal lobar degeneration (FTLD)-tau, such as corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), Pick’s Disease
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