Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer's disease paired helical filament tau

Matsuo, Eisuke; Shin, Ryong-Woon; Billingsley, Melvin L.; deVoorde, Andre Van; O’Connor, Michael J.; Trojanowski, John Q.; Lee, Virginia M.‐Y.

doi:10.1016/0896-6273(94)90264-x

Cited by 550 publications

(339 citation statements)

References 46 publications

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“…Storage of brains at 41C did not appear to affect the decrease in phospho-protein levels; however, it did appear to delay the degradation of some total proteins (Figures 2-6). Phosphorylation of the tau protein has been investigated in a number of studies; these studies have shown that while phosphorylation of most sites on tau are highly unstable during the PMI, some appear not to be affected to the same degree (Burack and Halpain, 1996;Gartner et al, 1998;Matsuo et al, 1994;Song et al, 1997). Our data are generally consistent withFand extendsFthis series of findings, suggesting that it may be difficult to measure the level of most phosphoproteins that are involved in intracellular signaling in post-mortem human brain specimens (where the average PMI is often longer than 24 h).…”

Section: Discussionmentioning

confidence: 99%

Post-mortem Interval Effects on the Phosphorylation of Signaling Proteins

Gould

Yuan

et al. 2002

Neuropsychopharmacol

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Post-mortem brain tissue provides a unique opportunity to uncover the genes or proteins involved in the pathophysiology of neuropsychiatric disorders. Protein phosphorylation is a common protein modification within intracellular signaling pathways that affects the distribution and function of protein, and has been hypothesized to be of major importance in both the pathophysiology and treatment of major neuropsychiatric disorders. Thus, we were interested in ascertaining the stability of the phosphorylated forms of proteins that are involved in cellular signaling. Antibodies against phospho-tyrosine, phospho-threonine, and phospho-PKA substrates were used to examine the PMI effects on the general amounts of proteins in their phosphorylated form. Phospho-specific antibodies for ERK, JNK, RSK, CREB, and ATF-2 were used to test the effects of PMI on specific proteins whose functioning are known to be regulated markedly by phosphorylation. We found that PMI rapidly decreased the levels of proteins in their phosphorylated states and also decreased the total levels of certain proteins. The PMI effects were observed in the samples stored at both 41C and room temperature, in both frontal cortex and hippocampus. Thus, it appears that measurements (such as two-dimensional gel electrophoresis and functional assays) that rely on the phosphorylation state of proteins would be extremely sensitive to PMI.

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Section: Discussionmentioning

confidence: 99%

Post-mortem Interval Effects on the Phosphorylation of Signaling Proteins

Gould

Yuan

et al. 2002

Neuropsychopharmacol

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“…When tau is phosphorylated, it is unable to polymerize tubulin into microtubules, which alters microtubule assembly and inhibits assembly promoted by normal tau (reviewed in [25] ). Most of these sites are phosphorylated during fetal development and even in the normal adult brain, but with lower stoichiometry or with different isoform expression [26,27] . Tau is hyperphosphorylated in the fetal brain because it contains higher than normal levels of tubulin needed for microtubule assembly suggesting that, at certain levels, phosphorylation is a normal mechanism used by neurons to maintain their activity and microtubule network [28] .…”

Section: Tau Phosphorylationmentioning

confidence: 99%

Tau-induced neurodegeneration: mechanisms and targets

Beharry

Cohen

et al. 2014

Neurosci. Bull.

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The accumulation of hyperphosphorylated tau is a common feature of several dementias. Tau is one of the brain microtubule-associated proteins. Here we discuss tau's functions in microtubule assembly and stabilization and with regard to its interactions with other proteins. We describe and analyze important post-translational modifications: hyperphosphorylation, ubiquitination, glycation, glycosylation, nitration, polyamination, proteolysis, acetylation, and methylation. We discuss how these post-translational modifi cations can alter tau's biological function. We analyze the role of mitochondrial health in neurodegeneration. We propose that microtubules could be a therapeutic target and review different approaches. Finally, we consider whether tau accumulation or its conformational change is related to tau-induced neurodegeneration, and propose a mechanism of neurodegeneration.Keywords: tau; phosphorylation; neurodegeneration; tauopathies; mitochondria; microtubules; tubulin; kinases; phosphatases; Alzheimer's disease ·Review· IntroductionAlzheimer 's disease (AD), first described by Alois Alzheimer more than 100 years ago [1] , is a progressive neurodegenerative disorder, characterized by an insidious onset with irreversible cognitive declines that lead to profound mental deterioration causing dementia [2] . Two major forms of lesion characterize AD: amyloid as diffuse neurotic plaques primarily composed of the Aβ peptide [3] , which are mainly insoluble deposits of protein and cellular material, and neurofibrillary tangles composed of fi lamentous hyperphosphorylated tau protein that builds up inside the neuron [4,5] .Amyloid precursor protein (APP) is a highly conserved transmembrane protein [6] believed to play a role in synapse formation, synaptic plasticity, and neuronal survival [7][8][9] .In AD, APP is cleaved by β-and γ-secretases leading to the overproduction of an abnormal proteolytic byproduct called amyloid beta (Aβ) [10] . Upon cleavage fragments of Aβ of various sizes are released from the membrane and aggregate in the brain to form the characteristic plaques seen in AD. Plaques are composed primarily of the 40 and 42 amino-acid peptide fragments Aβ40 and Aβ42, the latter being the predominant species. In addition, Aβ42 is more prone to aggregation and deposition and therefore the cause of neurotoxicity, as well as synaptic loss [11] .The second lesion in AD is formed by aggregates of the microtubule-associated protein tau, which forms intracytoplasmic neuronal inclusions or neurofibrillary tangles when hyperphosphorylated [12] . Tau is associated with neurons of the central nervous system [13] and its main biological function is promoting the in vitro assembly and stabilization of microtubules in the cytoskeleton [14,15] . Tau is a phosphoprotein that is encoded by a single gene, MAPT, located on chromosome 17q21 [16] ; alternative splicing of the gene produces six major isoforms expressed in the adult human brain [17] . Isoforms derive their names from the number of microtubule-binding repeat s...

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“…3 With maturation, hyperphosphorylated tau is less readily detected. [4][5][6] Under a variety of pathological conditions, including Alzheimer's disease, hyperphosphorylated tau self-aggregates into neurofibrillary tangles. In the AD brain, 19 phosphorylation sites have been identified in paired helical filament (PHF) tau throughout its 441 amino acids.…”

Section: Introductionmentioning

confidence: 99%

Development of an Assay to Screen for Inhibitors of Tau Phosphorylation by Cdk5

et al. 2004

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A high-throughput assay for tau phosphorylation by cdk5/p25 is described. Full-length recombinant tau was used as a substrate in the presence of saturating adenosine triphosphate (ATP). Using PHF-1, an antibody directed specifically against 2 tau phosphorylation epitopes (serine 396 and serine 404), an enzyme-linked immunosorbent assay (ELISA)-based colorimetric assay was formatted in 384-well plates. The assay was validated by measuring kinetic parameters for cdk5/p25 catalysis and known inhibitors. Rate constants for the site-specific phosphorylations at the PHF-1 epitopes were determined and suggested preferential phosphorylation at these sites. The performance of this assay in a high-throughput format was demonstrated and used to identify inhibitors of tau phosphorylation at specific epitopes phosphorylated by cdk5/p25. (Journal of Biomolecular Screening 2004:122-131)

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Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer's disease paired helical filament tau

Cited by 550 publications

References 46 publications

Post-mortem Interval Effects on the Phosphorylation of Signaling Proteins

Post-mortem Interval Effects on the Phosphorylation of Signaling Proteins

Tau-induced neurodegeneration: mechanisms and targets

Development of an Assay to Screen for Inhibitors of Tau Phosphorylation by Cdk5

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