1997
DOI: 10.1073/pnas.94.1.298
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Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: Sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau

Abstract: The microtubule-associated protein (MAP) tau is abnormally hyperphosphorylated in Alzheimer disease and accumulates in neurons undergoing neurofibrillary degeneration. In the present study, the associations of the Alzheimer-hyperphosphorylated tau (AD P-tau) with the high molecular weight MAPs (HMW-MAPs) MAP1 and MAP2 were investigated. The AD P-tau was found to aggregate with MAP1 and MAP2 in solution. The association of AD P-tau to the MAPs resulted in inhibition of MAP-promoted microtubule assembly. However… Show more

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Cited by 385 publications
(269 citation statements)
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“…We have shown that hyperphosphorylated tau inhibits normal tau-promoted tubulin assembly into microtubules and disrupts preformed microtubules [30] , probably by binding to normal tau [124] and other microtubule-associated proteins [125] . We have shown that phosphorylation of tau is suffi cient to promote tau self-assembly into fi laments [29] and that phosphorylation at Ser 199 and 262 and Thr 212 and 231 is sufficient to convert tau into an D-like protein in cells [101] and in vivo in transgenic Drosophila [126] .…”
Section: Discussionmentioning
confidence: 92%
“…We have shown that hyperphosphorylated tau inhibits normal tau-promoted tubulin assembly into microtubules and disrupts preformed microtubules [30] , probably by binding to normal tau [124] and other microtubule-associated proteins [125] . We have shown that phosphorylation of tau is suffi cient to promote tau self-assembly into fi laments [29] and that phosphorylation at Ser 199 and 262 and Thr 212 and 231 is sufficient to convert tau into an D-like protein in cells [101] and in vivo in transgenic Drosophila [126] .…”
Section: Discussionmentioning
confidence: 92%
“…30 Changes in tau protein, affecting stabilization of microtubules, are likely to impair axonal transport, 31,32 leading to changes in synaptic proteins and mitochondria axonal transport and ultimately culminating in "dying back" axons.…”
Section: ■ Tau Protein and Alzheimer's Diseasementioning
confidence: 99%
“…The phosphorylation state of tau-which critically controls its physiopathology leading to selfaggregation and/or reduced assembly and stability of microtubules used as tracks for axonal trafficking (Stoothoff et al, 2005)-is also regulated by NGF deprivation in vitro (Nuydens et al, 1997;Shelton and Johnson, 2001) as well as in vivo Capsoni et al, 2002a,b). Moreover, since tau controls the bidirectionality of axonal motor-driven transport in a concentration-dependent manner and differentially modulates the kinesin and dynein activity along microtubule tracks (Dixit et al, 2008), defective intracellular trafficking of cargoes, including NTFs, could be due to an increased expression level of this protein (Ebneth et al, 1998;Stamer et al, 2002;Mandelkow et al, 2003) or to its altered intracellular localization (Thies et al, 2007) or hyperphosphorylation (Tatebayashi et al, 2004;Alonso et al, 1997). To this regard, the finding that the retrograde transport of I-125-NGF and activated Trk receptors is inhibited by colchicine-a drug that interferes with the polymerization of microtubules (Watson et al, 1999;Sandow et al, 2000)-suggests that an altered function of tau protein may account for age-related deficiency of long-range NTF signaling in cholinergic neurons.…”
Section: Ngf and Tau Protein Metabolismmentioning
confidence: 99%