Tau in Alzheimer Disease and Related Tauopathies

Department of Neurochemistry, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, New York 10314-6399, USA.
Current Alzheimer research (Impact Factor: 3.89). 12/2010; 7(8):656-64. DOI: 10.2174/156720510793611592
Source: PubMed


Tau is the major microtubule associated protein (MAP) of a mature neuron. The other two neuronal MAPs are MAP1 and MAP2. An established function of MAPs is their interaction with tubulin and promotion of its assembly into microtubules and stabilization of the microtubule network. The microtubule assembly promoting activity of tau, a phosphoprotein, is regulated by its degree of phosphorylation. Normal adult human brain tau contains 2-3 moles phosphate/mole of tau protein. Hyperphosphorylation of tau depresses this biological activity of tau. In Alzheimer disease (AD) brain tau is ~three to four-fold more hyperphosphorylated than the normal adult brain tau and in this hyperphosphorylated state it is polymerized into paired helical filaments ([PHF) admixed with straight filaments (SF) forming neurofibrillary tangles. Tau is transiently hyperphosphorylated during development and during anesthesia and hypothermia but not to the same state as in AD brain. The abnormally hyperphosphorylated tau in AD brain is distinguished from transiently hyperphosphorylated tau by its ability (1) to sequester normal tau, MAP1 and MAP2 and disrupt microtubules, and (2) to self-assemble into PHF/SF. The cytosolic abnormally hyperphosphorylated tau, because of oligomerization, unlike normal tau, is sedimentable and on self-assembly into PHF/SF, loses its ability to sequester normal MAPs. Some of the tau in AD brain is truncated which also promotes its self-assembly. Tau mutations found in frontotemporal dementia apparently promote its abnormal hyperphosphorylation. Thus, the AD abnormally hyperphosphorylated tau (1) is distinguishable from both normal and transiently hyperphosphorylated taus, and (2) is inhibitory when in a cytosolic/oligomeric state but not when it is self-assembled into PHF/SF. Inhibition of abnormal hyperphosphorylation of tau offers a promising therapeutic target for AD and related tauopathies.

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Available from: Cheng-Xin Gong
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    • "The functions of tau proteins include stabilizing microtubules and maintaining axonal transport and neurogenesis. Abnormal phosphorylation (hyperphosphorylation) of tau proteins generates doublestranded helical filaments that can react with Aβ and apo E to form neurofibrillary tangles (Iqbal & Grundke-Iqbal, 2007;Iqbal et al., 2010), thereby inducing oxidative stress and inflammatory responses. The results of the present study reveal that MS and AK could significantly inhibit the expression of p-tau proteins, which effectively prevents the formation of neurofibrillary tangles. "
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    • "Tau protein acts as a substrate for phosphorylation at multiple sites by several different kinases e.g.GSK-3β, Cdk5, PKA, MARK etc. in vitro, but it is not clear which of these kinases are responsible for in vivo phosphorylation of tau in physiological or pathological conditions [33]. Under normal physiological conditions the reversible and transient phosphorylation of tau is involved in many neuronal functions such as axonal transport and neurite outgrowth, but pathological hyperphosphorylation of tau leads to oligomerization and fibrillization and decreased binding to microtubules [32] [33]. Despite a plethora of evidence from animal models (transgenic and chemical induced), cell based models and post-mortem brain of AD subjects supporting the 'Amyloid Cascade Hypothesis' or 'tauopathy', it is not fundamentally clear how these alterations of abnormal protein accumulation and aggregation are triggered in the aging brain especially in the case of sporadic AD. "
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