Levels of tau phosphorylation at different sites in Alzheimer disease brain

Ikura, Yuji; Kudo, Takashi; Tanaka, Toshihisa; Tanii, Hisashi; Grundke‐Iqbal, Inge; Iqbal, Khalid; Takeda, Masatoshi

doi:10.1097/00001756-199807130-00041

Cited by 23 publications

(14 citation statements)

References 5 publications

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“…Ser-262 is known as a major site for abnormal phosphorylation of PHF-tau in AD brain (47). Therefore, our finding would provide a new insight into the functional significance of the GSK-3␤-MARK2 pathway in the pathogenesis of AD.…”

Section: Discussionmentioning

confidence: 63%

GSK-3β Directly Phosphorylates and Activates MARK2/PAR-1

Kosuga¹,

Tashiro²,

Kajioka

et al. 2005

Journal of Biological Chemistry

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In Alzheimer disease (AD), the microtubule-associated protein tau is found hyperphosphorylated in paired helical filaments. Among many phosphorylated sites in tau, Ser-262 is the major site for abnormal phosphorylation of tau in AD brain. The kinase known to phosphorylate this particular site is MARK2, whose activation mechanism is yet to be studied. Our first finding that treatment of cells with LiCl, a selective inhibitor of another major tau kinase, glycogen synthase kinase-3␤ (GSK-3␤), inhibits phosphorylation of Ser-262 of tau led us to investigate the possible involvement of GSK-3␤ in MARK2 activation. In vitro kinase reaction revealed that recombinant GSK-3␤ indeed phosphorylates MARK2, whereas it failed to phosphorylate Ser-262 of tau. Our further findings led us to conclude that GSK-3␤ phosphorylates MARK2 on Ser-212, one of the two reported phosphorylation sites (Thr-208 and Ser-212) found in the activation loop of MARK2. Down-regulation of either GSK-3␤ or MARK2 by small interfering RNAs suppressed the level of phosphorylation on Ser-262. These results, respectively, indicated that GSK-3␤ is responsible for phosphorylating Ser-262 of tau through phosphorylation and activation of MARK2 and that the phosphorylation of tau at this particular site is predominantly mediated by a GSK-3␤-MARK2 pathway. These findings are of interest in the context of the pathogenesis of AD.

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Section: Discussionmentioning

confidence: 63%

GSK-3β Directly Phosphorylates and Activates MARK2/PAR-1

Kosuga¹,

Tashiro²,

Kajioka

et al. 2005

Journal of Biological Chemistry

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“…Although GSK-3␤ is responsible for phosphorylating Ser202 (Mandelkow et al, 1992;Ishiguro et al, 1993), the major site for abnormal phosphorylation of tau resulting in formation of paired helical filaments (PHFs) in AD (Ikura et al, 1998), it is uncertain whether the PDTC-induced reduction we observed in Ser202 phosphorylation (AT8 immunoreactivity) contributes to the improved cognitive functions, because PHFs cannot be found in transgenic APP or APP/PS1 mice and we could not detect reduction in AT8-immunoreactive dystrophic neurites around A␤ deposits. We also observed a tendency for decreased tau phosphorylation in PDTC-treated APP/PS1 mice by using AT100 antibody, which detects phosphorylation of Ser212 (a target of several kinases, including GSK-3␤) and Thr214, supporting the notion that PDTC affects GSK-3␤ activity in neurons of APP/PS1 mice.…”

Section: Discussionmentioning

confidence: 81%

Pyrrolidine Dithiocarbamate Activates Akt and Improves Spatial Learning in APP/PS1 Mice without Affecting β-Amyloid Burden

Malm¹,

Iivonen²,

Goldsteins³

et al. 2007

J. Neurosci.

146

108

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Pyrrolidine dithiocarbamate (PDTC) is a clinically tolerated inhibitor of nuclear factor-B (NF-B), antioxidant and antiinflammatory agent, which provides protection in brain ischemia models. In neonatal hypoxia-ischemia model, PDTC activates Akt and reduces activation of glycogen synthase kinase 3␤ (GSK-3␤). Because chronic inflammation, oxidative stress, and increased GSK-3␤ activity are features of Alzheimer's disease (AD) pathology, we tested whether PDTC reduces brain pathology and improves cognitive function in a transgenic animal model of AD. A 7 month oral treatment with PDTC prevented the decline in cognition in AD mice without altering ␤-amyloid burden or gliosis. Moreover, marked oxidative stress and activation of NF-B were not part of the brain pathology. Instead, the phosphorylated form of GSK-3␤ was decreased in the AD mouse brain, and PDTC treatment increased the phosphorylation of Akt and GSK-3␤. Also, PDTC treatment increased the copper concentration in the brain. In addition, PDTC rescued cultured hippocampal neurons from the toxicity of oligomeric A␤ and reduced tau phosphorylation in the hippocampus of AD mice. Finally, astrocytic glutamate transporter GLT-1, known to be regulated by Akt pathway, was decreased in the transgenic AD mice but upregulated back to the wild-type levels by PDTC treatment. Thus, PDTC may improve spatial learning in AD by interfering with Akt-GSK pathway both in neurons and astrocytes. Because PDTC is capable of transferring external Cu 2ϩ into a cell, and, in turn, Cu 2ϩ is able to activate Akt, we hypothesize that PDTC provides the beneficial effect in transgenic AD mice through Cu 2ϩ -activated Akt pathway.

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“…Tau phosphorylation at S202/T205, as detected by the AT8 antibody , is a common feature in tauopathies and accumulates in fairly late neurofibrillary tangle development (Ikura et al 1998;Wada et al 1998;Augustinack et al 2002;Ferrer et al 2002;Wray et al 2008;Han et al 2009). Thus, increased AT8 signal is predicted to correlate with enhanced toxicity found in white and white 1 brown backgrounds; however, AT8 immunoreactivity was reduced in w 1118 homozygous flies as compared to w 1 /w 1118 heterozygotes ( Figure 4A).…”

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confidence: 99%

Interaction Between Eye Pigment Genes and Tau-Induced Neurodegeneration inDrosophila melanogaster

Ambegaokar

Jackson

2010

Genetics

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Null mutations in the genes white and brown, but not scarlet, enhance a rough eye phenotype in a Drosophila melanogaster model of tauopathy; however, adding rosy mutations suppresses these effects. Interaction with nucleotide-derived pigments or increased lysosomal dysregulation are potential mechanisms. Finally, tau toxicity correlates with increased GSK-3b activity, but not with tau phosphorylation at Ser202/Thr205.

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Levels of tau phosphorylation at different sites in Alzheimer disease brain

Cited by 23 publications

References 5 publications

GSK-3β Directly Phosphorylates and Activates MARK2/PAR-1

GSK-3β Directly Phosphorylates and Activates MARK2/PAR-1

Pyrrolidine Dithiocarbamate Activates Akt and Improves Spatial Learning in APP/PS1 Mice without Affecting β-Amyloid Burden

Interaction Between Eye Pigment Genes and Tau-Induced Neurodegeneration inDrosophila melanogaster

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