Phylogenetic diversity of the expression of the microtubule-associated protein tau: implications for neurodegenerative disorders

Janke, Carsten; Beck, Mike; Stahl, Tobias; Holzer, Max; Brauer, K; Bigl, Volker; Arendt, Thomas

doi:10.1016/s0169-328x(99)00079-0

Cited by 99 publications

(99 citation statements)

References 58 publications

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“…By using 3-repeat and 4-repeat tau-specific antibodies (28), we assessed whether tau splice ratios were altered by lithium treatment. 4-Repeat tau did not change and 3-repeat tau was undetectable (data not shown), which is not surprising given that tau in adult mouse brain is exclusively 4-repeat (36) and that JNPL3 mice express only 4-repeat human tau with no regulatory sequence. Thus, our results are not due to a shift in tau isoform composition that might affect the pathology.…”

Section: Resultsmentioning

confidence: 58%

Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degenerationin vivo

Noble

Planel

Zehr

et al. 2005

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

646

471

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Neurofibrillary tangles composed of hyperphosphorylated, aggregated tau are a common pathological feature of tauopathies, including Alzheimer's disease. Abnormal phosphorylation of tau by kinases or phosphatases has been proposed as a pathogenic mechanism in tangle formation. To investigate whether kinase inhibition can reduce tauopathy and the degeneration associated with it in vivo, transgenic mice overexpressing mutant human tau were treated with the glycogen synthase kinase-3 (GSK-3) inhibitor lithium chloride. Treatment resulted in significant inhibition of GSK-3 activity. Lithium administration also resulted in significantly lower levels of phosphorylation at several epitopes of tau known to be hyperphosphorylated in Alzheimer's disease and significantly reduced levels of aggregated, insoluble tau. Administration of a second GSK-3 inhibitor also correlated with reduced insoluble tau levels, supporting the idea that lithium exerts its effect through GSK-3 inhibition. Levels of aggregated tau correlated strongly with degree of axonal degeneration, and lithium-chloride-treated mice showed less degeneration if administration was started during early stages of tangle development. These results support the idea that kinases are involved in tauopathy progression and that kinase inhibitors may be effective therapeutically.phosphorylation ͉ neurofibrillary tangles ͉ Alzheimer's disease ͉ tau protein

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Section: Resultsmentioning

confidence: 58%

Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degenerationin vivo

Noble

Planel

Zehr

et al. 2005

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

646

471

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“…Here, despite sustained mild hyperphosphorylation of tau for 30 d and massive late hyperphosphorylation, we could not detect aggregated tau in mice, and tau binding to MTs was affected only at 40 d after STZ treatment. The differences in sequence and isoform composition between human and mouse tau (Janke et al, 1999), cannot explain the lack of tau aggregates in nontransgenic mice, because rodent tau can form PHFs as readily as human tau after being hyperphosphorylated in vitro (Chohan et al, 2005). Thus, absence of aggregates could be attributable to insufficient levels of total tau phosphorylation in the STZ model, or to insufficient levels of phosphorylation at epitopes promoting aggregation.…”

Section: Discussionmentioning

confidence: 99%

Insulin Dysfunction InducesIn VivoTau Hyperphosphorylation through Distinct Mechanisms

Planel¹,

Tatebayashi²,

Miyasaka³

et al. 2007

J. Neurosci.

226

172

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Hyperphosphorylated tau is the major component of paired helical filaments in neurofibrillary tangles found in Alzheimer's disease (AD) brains, and tau hyperphosphorylation is thought to be a critical event in the pathogenesis of the disease. The large majority of AD cases is late onset and sporadic in origin, with aging as the most important risk factor. Insulin resistance, impaired glucose tolerance, and diabetes mellitus (DM) are other common syndromes in the elderly also strongly age dependent, and there is evidence supporting a link between insulin dysfunction and AD. To investigate the possibility that insulin dysfunction might promote tau pathology, we induced insulin deficiency and caused DM in mice with streptozotocin (STZ). A mild hyperphosphorylation of tau could be detected 10, 20, and 30 d after STZ injection, and a massive hyperphosphorylation of tau was observed after 40 d. The robust hyperphosphorylation of tau was localized in the axons and neuropil, and prevented tau binding to microtubules. Neither mild nor massive tau phosphorylation induced tau aggregation. Body temperature of the STZ-treated mice did not differ from control animals during 30 d, but dropped significantly thereafter. No change in ␤-amyloid (A␤) precursor protein (APP), APP C-terminal fragments, or A␤ levels were observed in STZ-treated mice; however, cellular protein phosphatase 2A activity was significantly decreased. Together, these data indicate that insulin dysfunction induced abnormal tau hyperphosphorylation through two distinct mechanisms: one was consequent to hypothermia; the other was temperature-independent, inherent to insulin depletion, and probably caused by inhibition of phosphatase activity.

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“…Normal fetal and adult brain are groups of multiply phosphorylated and thermostable proteins generated by alternative splicing of exons 2 and 3 in the amino-terminal region and exon 10 in the microtubule-binding region of the single gene located on chromosome 17q21 (2,6). Thus, six human (7,8), four bovine (8,9), and three rat (8,10) isoforms are generated. Bovine isoforms contain either 3 or 4 repeats and 1 or 2 amino-terminal inserts.…”

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confidence: 99%

τ kinases in the rat heat shock model: Possible implications for Alzheimer disease

Shanavas

Papasozomenos

2000

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

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We have previously shown, by using the phosphate-dependent anti-antibodies Tau-1 and PHF-1, that heat shock induces rapid dephosphorylation of followed by hyperphosphorylation in female rats. In this study, we analyzed in forebrain homogenates from female Sprague-Dawley rats the activities of extracellular signal regulated kinase 1͞2 (ERK1͞2), c-Jun NH2-terminal kinase (JNK), glycogen synthase kinase-3␤ (GSK-3␤), cyclin-dependent kinase 5 (Cdk5), cAMP-dependent protein kinase A (PKA), and Ca 2؉ ͞calmodulin-dependent protein kinase II (CaMKII) at 0 (n ‫؍‬ 5), 3 (n ‫؍‬ 4), 6 (n ‫؍‬ 5), and 12 (n ‫؍‬ 5) h after heat shock and in non-heat-shocked controls (n ‫؍‬ 5). Immunoprecipitation kinase assays at 0 h showed suppression of the activities of all kinases except of GSK-3␤, which showed increased activity. At 3-6 h, the activities of ERK1͞2, JNK, Cdk5, and GSK-3␤ toward selective substrates were increased; however, only JNK, Cdk5, and GSK-3␤ but not ERK1͞2 were overactivated toward purified bovine . At 3-6 h, kinase assays specific for PKA and CaMKII showed no increased activity toward either or selective substrates. All of eight anti-antibodies tested showed dephosphorylation at 0 h and hyperphosphorylation at 3-6 h, except for 12E8, which showed hyperphosphorylation also at 0 h. Immunoblot analysis using activity-dependent antibodies against ERK1͞2, JNK, and GSK-3␤ confirmed the above data. Increased activation and inhibition of kinases after heat shock were statistically significant in comparison with controls. Because is hyperphosphorylated in Alzheimer disease these findings suggest that JNK, GSK-3␤, and Cdk5 may play a role in its pathogenesis.

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Phylogenetic diversity of the expression of the microtubule-associated protein tau: implications for neurodegenerative disorders

Cited by 99 publications

References 58 publications

Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degenerationin vivo

Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degenerationin vivo

Insulin Dysfunction InducesIn VivoTau Hyperphosphorylation through Distinct Mechanisms

τ kinases in the rat heat shock model: Possible implications for Alzheimer disease

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