Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans

Goedert, Michel; Jakes, Ross; Spillantini, M. G.; Hasegawa, Masato; Smith, Michael J.; Crowther, R. Anthony

doi:10.1038/383550a0

Cited by 946 publications

(930 citation statements)

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“…One difference from AD is that, in familial MSTD, antibody 12E8 stained not only NFTs, NTs, and glialfibrillary tangles but also numerous granular deposits in neurons and glial cells. As in AD (43), nerve cells that were immunoreactive for hyperphosphorylated tau also stained with the heparan sulfate antibody 10E4. In familial MSTD, this was also the case for glial cells with tau pathology, suggesting that the coexistence of heparan sulfate and tau immunoreactivities may be a general phenomenon in neurodegenerative diseases with tau pathology.…”

Section: Discussionmentioning

confidence: 99%

“…In familial MSTD, this was also the case for glial cells with tau pathology, suggesting that the coexistence of heparan sulfate and tau immunoreactivities may be a general phenomenon in neurodegenerative diseases with tau pathology. Recent findings suggest that an interaction between tau protein and sulfated glycosaminoglycans may be a necessary event in tau filament formation (43).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Familial multiple system tauopathy with presenile dementia: A disease with abundant neuronal and glial tau filaments

Spillantini¹,

Goedert

Crowther

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

319

214

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Neurofibrillary lesions made of hyperphosphorylated microtubule-associated protein tau constitute not only one of the defining neuropathological features of Alzheimer disease but also are present in a number of other neurodegenerative diseases with dementia. Here we describe a novel autosomal dominant disease named familial ''multiple system tauopathy with presenile dementia,'' which is characterized by abundant fibrillary deposits of tau protein in both neurons and glial cells. There are no detectable deposits of ␤-amyloid. The tau deposits are in the form of twisted filaments that differ in diameter and periodicity from the paired helical filaments of Alzheimer disease. They are stained by both phosphorylation-independent and -dependent anti-tau antibodies. Moreover, tau immunoreactivity coexists with heparan sulfate in affected nerve and glial cells. Tau protein extracted from filaments of familial multiple system tauopathy with presenile dementia shows a minor 72-kDa band and two major bands of 64 and 68 kDa that contain mainly hyperphosphorylated four-repeat tau isoforms of 383 and 412 amino acids.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Familial multiple system tauopathy with presenile dementia: A disease with abundant neuronal and glial tau filaments

Spillantini¹,

Goedert

Crowther

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

319

214

View full text Add to dashboard Cite

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“…Formation of PHFs in vitro can be accomplished in a phosphorylation-independent manner via interaction of sulfated glycosaminoglycans (such as heparin and heparan sulfate) with microtubule-binding domains of adjacent tau three-and four-repeat monomers [76] . The interplay between phosphorylation as a targeting event, tau glycation, oxidation, and heparan-mediated PHF formation remains to be elucidated.…”

Section: Other Post-translational Modifi Cationsmentioning

confidence: 99%

“…PHF-tau is also modified by glycolipids. Mass spectrometry and NMR analysis of acid-resistant PHF tau revealed the presence of several glycolipids consisting of glucose pentamers, hexamers, and tridecamers variably associated with esterified fatty acids (C 14 -C 20 ) [13] .Formation of PHFs in vitro can be accomplished in a phosphorylation-independent manner via interaction of sulfated glycosaminoglycans (such as heparin and heparan sulfate) with microtubule-binding domains of adjacent tau three-and four-repeat monomers [76] . The interplay between phosphorylation as a targeting event, tau glycation, oxidation, and heparan-mediated PHF formation remains to be elucidated.…”

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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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“…In vitro studies have shown that tau phosphorylation is not necessary to drive tau into PHFs. 140,141 On the contrary, phosphorylation of the KXGS motifs in the repeat region inhibits tau aggregation in vitro. 86 Tau comprises two hydrophobic hexapeptide motifs 144,145 in the repeat domains (275VQIINK280 at the beginning of R2 and 306VQIVYK311 at the beginning of R3) that form a cross ␤-structure and make up the PHF core.…”

Section: Antiaggregation Strategiesmentioning

confidence: 99%

Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

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Summary:Neurofibrillary tangles are a characteristic hallmark of Alzheimer's and other neurodegenerative diseases, such as Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). These diseases are summarized as tauopathies, because neurofibrillary tangles are composed of intracellular aggregates of the microtubule-associated protein tau. The molecular mechanisms of tau-mediated neurotoxicity are not well understood; however, pathologic hyperphosphorylation and aggregation of tau play a central role in neurodegeneration and neuronal dysfunction. The present review, therefore, focuses on therapeutic approaches that aim to inhibit tau phosphorylation and aggregation or to dissolve preexisting tau aggregates. Further experimental therapy strategies include the enhancement of tau clearance by activation of proteolytic, proteasomal, or autophagosomal degradation pathways or anti-tau directed immunotherapy. Hyperphosphorylated tau does not bind microtubules, leading to microtubule instability and transport impairment. Pharmacological stabilization of microtubule networks might counteract this effect. In several tauopathies there is a shift toward four-repeat tau isoforms, and interference with the splicing machinery to decrease four-repeat splicing might be another therapeutic option.

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Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans

Cited by 946 publications

References 31 publications

Familial multiple system tauopathy with presenile dementia: A disease with abundant neuronal and glial tau filaments

Familial multiple system tauopathy with presenile dementia: A disease with abundant neuronal and glial tau filaments

Tau-induced neurodegeneration: mechanisms and targets

Tau-Based Treatment Strategies in Neurodegenerative Diseases

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