Tau-tubulin kinase 1 (TTBK1), a neuron-specific tau kinase candidate, is involved in tau phosphorylation and aggregation

Neurofibrillary tangles, which are major pathological hallmarks of Alzheimer's disease (AD), are composed of paired helical filaments (PHFs) containing hyperphosphorylated tau. Specific kinases regulate tau phosphorylation and are closely linked to the pathogenesis of AD. We have characterized a human tau-tubulin kinase 1 (TTBK1) gene located on chromosome 6p21.1. TTBK1 is a serine/threonine/tyrosine kinase that is conserved among species and belongs to the casein kinase 1 superfamily. It is specifically expressed in the brain, especially in the cytoplasm of cortical and hippocampal neurons. TTBK1 phosphorylates tau proteins in both a Mg2+- and a Mn2+-dependent manner. Phosphopeptide mapping and immunoblotting analysis confirmed a direct tau phosphorylation by TTBK1 at Ser198, Ser199, Ser202 and Ser422, which are also phosphorylated in PHFs. TTBK1 also induces tau aggregation in human neuronal cells in a dose-dependent manner. We conclude that TTBK1 is a neuron-specific dual kinase involved in tau phosphorylation at AD-related sites and is also associated with tau aggregation.     

Brain glucose transporters, O-GlcNAcylation and phosphorylation of tau in diabetes and Alzheimer's disease

Type 2 diabetes mellitus (T2DM) increases the risk for Alzheimer's disease (AD), but the underlying mechanism is unknown. In this study, we determined the levels of major brain glucose transporters, O -GlcNAcylation and phosphorylation of tau in the postmortem brain tissue from frontal cortices of 7 controls, 11 T2DM subjects, 10 AD subjects and 8 additional subjects who had both T2DM and AD. We found that the neuronal glucose transporter 3 was decreased to a bigger extent in T2DM brain than in AD brain. The O -GlcNAcylation levels of global proteins and of tau were also decreased in T2DM brain as seen in AD brain. Phosphorylation of tau at some of the AD abnormal hyperphosphorylation sites was increased in T2DM brain. These results suggest that T2DM may contribute to the increased risk for AD by impairing brain glucose uptake/metabolism and, consequently, down-regulation of O -GlcNAcylation, which facilitates abnormal hyperphosphorylation of tau.     

Excitatory amino acid transporter 2 associates with phosphorylated tau and is localized in neurofibrillary tangles of tauopathic brains

Phosphorylated tau (p-tau) is the principal component of neurofibrillary tangles, a pathological hallmark, and likely plays a neurotoxic role in tauopathies including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). We subjected brains from autopsy cases of AD, PSP, and CBD to a variety of immunohistochemical, immunoblotting, and pull-down assays. In this study, we show that excitatory amino acid transporter 2 (EAAT2) preferentially interacted with phosphorylated tau and was localized in neurofibrillary tangles in the brains of such patients. These results strongly indicate that EAAT2 acts in tauopathy-related neurodegeneration, and abnormalities in glutamate transport play an important role in the pathogenesis of tauopathies.

Structured summary

MINT-7148349, MINT-7148361:TAU (uniprotkb:P10636) physically interacts (MI:0914) with EAAT2 (uniprotkb:P43004) by pull-down (MI:0096)MINT-7148372, MINT-7148384:TAU (uniprotkb:P10636) physically interacts (MI:0914) with EAAT2 (uniprotkb:P43004) by anti bait coimmunoprecipitation (MI:0006)