Tau Phosphorylated at Tyrosine 394 is Found in Alzheimer's Disease Tangles and can be a Product of the Abl-Related Kinase, Arg

Tremblay, Matthew A.; Acker, Christopher M.; Davies, Peter

doi:10.3233/jad-2010-1271

Cited by 93 publications

(86 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…AT8 ELISA Assay-A 96-well half area high binding ELISA plate (Costar) was coated with 2 g/ml AT8 antibody (13) in PBS overnight at 4°C. The plate was washed with PBS buffer containing 0.05% Tween 20 (PBST) three times and blocked with BB3 blocking buffer (ImmunoChemistry Technology).…”

Section: Methodsmentioning

confidence: 99%

Passive Immunization with Anti-Tau Antibodies in Two Transgenic Models

Chai

Murray

et al. 2011

Journal of Biological Chemistry

Self Cite

303

141

View full text Add to dashboard Cite

Background:Recent active immunization studies have raised the possibility of modulating Tau pathology. Results: Peripheral administration of two antibodies against pathological Tau forms reduces Tau pathology and improves functional outcomes. Conclusion: Passive immunotherapy is effective at preventing the buildup of intracellular Tau pathology. Significance: Tau immunotherapy should be considered as a therapeutic approach for the treatment of Alzheimer disease and other tauopathies.

show abstract

Section: Methodsmentioning

confidence: 99%

Passive Immunization with Anti-Tau Antibodies in Two Transgenic Models

Chai

Murray

et al. 2011

Journal of Biological Chemistry

Self Cite

303

141

View full text Add to dashboard Cite

show abstract

“…Nonetheless, it is certainly possible that proteolytic cleavage at amino acid 391 in AD recognized by the MN423 antibody 44 might eliminate TaunY394 reactivity, should it occur late in NFT evolution. Alternatively, phosphorylation at Y394 has previously been reported in AD, 45 and this may explain the limited nitration at this site. The highly electronegative orthophosphate group likely would not permit the addition of a nitro group at the meta position of the same tyrosine ring.…”

Section: Timing Of Nitration During Tangle Evolution In Ad Pathogenesismentioning

confidence: 99%

Tyrosine Nitration within the Proline-Rich Region of Tau in Alzheimer's Disease

Reyes

Vana

et al. 2011

The American Journal of Pathology

View full text Add to dashboard Cite

A substantial body of evidence suggests that nitrative injury contributes to neurodegeneration in Alzheimer's disease (AD) and other neurodegenerative disorders. Previously, we showed in vitro that within the tau protein the N-terminal tyrosine residues (Y18 and Y29) are more susceptible to nitrative modifications than other tyrosine sites (Y197 and Y394). Using sitespecific antibodies to nitrated tau at Y18 and Y29, we identified tau nitrated in both glial (Y18) and neuronal (Y29) tau pathologies. In this study, we report the characterization of two novel monoclonal antibodies, Tau-nY197 and Tau-nY394, recognizing tau nitrated at Y197 and Y394, respectively. By Western blot analysis, Tau-nY197 labeled soluble tau and insoluble paired helical filament proteins (PHF-tau) nitrated at Y197 from control and AD brain samples. TaunY394 failed to label soluble tau isolated from control or severe AD samples, but labeled insoluble PHF-tau to a limited extent. Immunohistochemical analysis using Tau-nY197 revealed the hallmark tau pathology associated with AD; Tau-nY394 did not detect any pathological lesions characteristic of the disorder. These data suggest that a subset of the hallmark pathological inclusions of AD contain tau nitrated at Y197. However, nitration at Y197 was also identified in soluble tau from all control samples, including those at Braak stage 0, suggesting that nitration at this site in the proline-rich region of tau may have normal biological functions in the human brain.

show abstract

“…Out of the fi ve tyrosines 18, 29, 197, 310, and 394 (according to tau441), 18,197, and 394 are phosphorylated in the AD brain whereas 394 is the only residue that has been described to date to be phosphorylated under physiological conditions. PHF samples from AD brains have been analyzed and phosphorylation at tyrosines 18 and 394 has been reported [55] . Abl is known to phosphorylate tyrosine 394 (Y394) and, recently, the Tyr kinase Arg, which plays a role in the oxidative stress response and neuronal development, was also shown to phosphorylate Y394 in a manner independent of Abl activity [55] .…”

Section: Tau Phosphatases Phosphatases Counterbalancementioning

confidence: 99%

“…PHF samples from AD brains have been analyzed and phosphorylation at tyrosines 18 and 394 has been reported [55] . Abl is known to phosphorylate tyrosine 394 (Y394) and, recently, the Tyr kinase Arg, which plays a role in the oxidative stress response and neuronal development, was also shown to phosphorylate Y394 in a manner independent of Abl activity [55] . In a transgenic mouse model of AD, tyrosine 18-phosphorylated tau occurs in neurofibrillary tangles and the expression of Fyn is increased in these cases [56,57] .…”

Section: Tau Phosphatases Phosphatases Counterbalancementioning

confidence: 99%

Tau-induced neurodegeneration: mechanisms and targets

Beharry

Cohen

et al. 2014

Neurosci. Bull.

View full text Add to dashboard Cite

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...

show abstract

Tau Phosphorylated at Tyrosine 394 is Found in Alzheimer's Disease Tangles and can be a Product of the Abl-Related Kinase, Arg

Cited by 93 publications

References 43 publications

Passive Immunization with Anti-Tau Antibodies in Two Transgenic Models

Passive Immunization with Anti-Tau Antibodies in Two Transgenic Models

Tyrosine Nitration within the Proline-Rich Region of Tau in Alzheimer's Disease

Tau-induced neurodegeneration: mechanisms and targets

Contact Info

Product

Resources

About