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, Oct 04, 2015
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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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    ABSTRACT: Alzheimer's disease (AD), the major cause of dementia among the elderly world-wide, manifests in familial and sporadic forms, and the latter variety accounts for the majority of the patients affected by this disease. The etiopathogenesis of sporadic AD is complex and uncertain. The autopsy studies of AD brain have provided limited understanding of the antemortem pathogenesis of the disease. Experimental AD research with transgenic animal or various cell based models has so far failed to explain the complex and varied spectrum of AD dementia. The review, therefore, emphasizes the importance of AD related risk factors, especially those with metabolic implications, identified from various epidemiological studies, in providing clues to the pathogenesis of this complex disorder. Several metabolic risk factors of AD like hypercholesterolemia, hyperhomocysteinemia and type 2 diabetes have been studied extensively both in epidemiology and experimental research, while much less is known about the role of adipokines, pro-inflammatory cytokines and vitamin D in this context. Moreover, the results from many of these studies have shown a degree of variability which has hindered our understanding of the role of AD related risk factors in the disease progression. The review also encompasses the recent recommendations regarding clinical and neuropathological diagnosis of AD and brings out the inherent uncertainty and ambiguity in this area which may have a distinct impact on the outcome of various population-based studies on AD-related risk factors.
    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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    ABSTRACT: Disorganization of the cytoskeleton of neurons has major consequences on the transport of neurotransmitters via the microtubule network. The interaction of cytoskeleton proteins (actin and tubulin) was studied in neuronal SK-N-BE cells treated with tetracosanoic acid (C24:0), which is cytotoxic and increased in Alzheimer's disease patients. When SK-N-BE cells were treated with C24:0, mitochondrial dysfunctions and a non-apoptotic mode of cell death were observed. Fluorescence microscopy revealed shrunken cells with perinuclear condensation of actin and tubulin. Impact of C24:0 on actin-microtubule interaction in human neuronal SK-N-BE cells: evaluation by FRET confocal spectral imaging microscopy after dual staining with rhodamine-phalloidin and tubulin tracker green After staining with rhodamine-phalloidin and with an antibody raised against α-/β-tubulin, modifications of F-actin and α-/β-tubulin levels were detected by flow cytometry. Lower levels of α-tubulin were found by Western blotting. In C24:0-treated cells, spectral analysis and fluorescence recovery after photobleaching (FRAP) measured by confocal microscopy proved the existence of fluorescence resonance energy transfer (FRET) when actin and tubulin were stained with tubulin tracker and rhodamine-phalloidin demonstrating actin and tubulin co-localization/interaction. In control cells, no FRET was observed. Our data demonstrate quantitative changes in actin and tubulin, and modified interactions between actin and tubulin in SK-N-BE cells treated with C24:0. They also show that FRET confocal imaging microscopy is an interesting method for specifying the impact of cytotoxic compounds on cytoskeleton proteins.
    05/2015; 30(1):33-46. DOI:10.11138/FNeur/2015.30.1.033
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