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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    • "Indeed , it has many proteoforms ( Smith and Kelleher , 2013 ) : six isoforms ( ranging from 352 to 441 amino acids ) , truncated forms and forms widely modified post - translationally by glycosylation , oxidation , and phosphorylation at more than 80 sites ( Iqbal et al . , 2010 ; Hanger et al . , 2014 ) . As phosphorylation and any other post - translational modification of tau peptides induce a mass shift that results in an underestimation of total tau concentration measured by LC - MS / MS , it could be suspected that LC - MS / MS results should have been even higher . This explains why total tau concentrati"
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    ABSTRACT: Tau protein concentration in cerebrospinal fluid (CSF) is currently used as a sensitive and specific biomarker for Alzheimer's disease. Its detection currently relies on ELISA but the perspective of using mass spectrometry (MS) to detect its different proteoforms represents an interesting alternative. This is however an analytical challenge because of its low concentration in the CSF, a biological fluid collected in small volume by lumbar puncture, and with a high structural heterogeneity. To overcome these issues, instead of using immunocapture as previously done, we rather relied on an original two steps pre-fractionation technique of CSF: perchloric acid followed by micro solid phase extraction (µSPE). We could then measure seven tau trypsic peptides by Multiple Reaction Monitoring (MRM) on a triple quadrupole mass spectrometer. Quantification was performed using isotopically labelled 15N- recombinant Tau protein as internal standard and validated using CSF pools with low, medium or high tau concentrations. Repeatability, intermediate precision, linearity, limit of quantification and recovery were calculated for the different peptides. This new MRM assay, which allowed for the first time CSF tau protein quantification without immunocapture, has important potential application to follow tau metabolism in both diagnostic and therapeutic research.
    Frontiers in Neuroscience 09/2015; 9:1-8. DOI:10.3389/fnins.2015.00302 · 3.66 Impact Factor
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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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    Aging and Disease 08/2015; 6(4):282-99. DOI:10.14336/AD.2014.002 · 3.07 Impact Factor
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    • "These include hyperphosphorylation of tau, a neuronal protein involved in microtubule stabilization that also contributes to microtubule dynamics and axonal transport (Cavallucci et al., 2012; Lee and Leugers, 2012). The pathogenic hyperphosphorylated form of tau favors disorganization of microtubules (made up of α-and β-tubulin subunits) (Iqbal et al., 2010). In AD, microtubules and actin microfilaments, which are major components of the cytoskeleton of neurons and contribute to organelle trafficking as well as to the transport of neurotransmitters (Schrader et al., 2003; von Braun and Schleiff, 2007), are frequently altered (Bamburg and Bloom, 2009). "
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    05/2015; 30(1):33-46. DOI:10.11138/FNeur/2015.30.1.033
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