Starvation induces tau hyperphosphorylation in mouse brain: implications for Alzheimer's disease

Yanagisawa, Masahiro; Planel, Emmanuel; Ishiguro, Koichi; Fujita, Shinobu C.

doi:10.1016/s0014-5793(99)01480-5

Cited by 114 publications

(92 citation statements)

References 37 publications

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“…1-4). As described qualitatively (16), tau undergoes phosphorylation and dephosphorylation, illustrated here by phosphorylation-dependent anti-tau antibody AT8 (Fig. 1, A1 and B1).…”

Section: Starvation Up-regulates Activating Phosphorylation Of Mapk Asupporting

confidence: 57%

“…Reduced glucose metabolism is associated with certain regions of the brain of probable and preclinical AD subjects (19,20), and is considered by some as aggravating, if not causative in the development of AD (21). These data, combined with the observations that starvation induces tau hyperphosphorylation at many PHF-tau epitopes, and with a regional selectivity analogous to that in AD, suggest that a common mechanism might be mobilized in starvation and AD for tau hyperphosphorylation (16).…”

mentioning

confidence: 99%

“…Tau hyperphosphorylation is a physiological reversible response of the brain to stressful conditions like cold water stress 2 (14), heat-shock (15), or starvation (16). Starvation induces decreases in circulating glucose, insulin, and leptin, and increases in corticosterone (17), and results in a large decrease of glucose in many parts of the brain (18).…”

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confidence: 99%

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Inhibition of Protein Phosphatase 2A Overrides Tau Protein Kinase I/Glycogen Synthase Kinase 3β and Cyclin-dependent Kinase 5 Inhibition and Results in Tau Hyperphosphorylation in the Hippocampus of Starved Mouse

Planel¹,

Yasutake

Fujita

et al. 2001

Journal of Biological Chemistry

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Hyperphosphorylated tau is the major component of paired helical filaments in neurofibrillary tangles found in Alzheimer's disease (AD) brain. Starvation of adult mice induces tau hyperphosphorylation at many paired helical filaments sites and with a similar regional selectivity as those in AD, suggesting that a common mechanism may be mobilized. Here we investigated the mechanism of starvation-induced tau hyperphosphorylation in terms of tau kinases and Ser/Thr protein phosphatases (PP), and the results were compared with those reported in AD brain. During starvation, tau hyperphosphorylation at specific epitopes was accompanied by decreases in tau protein kinase I/glycogen synthase kinase 3␤ (TPKI/ GSK3␤), cyclin-dependent kinase 5 (cdk5), and PP2A activities toward tau. These results demonstrate that the activation of TPKI/GSK3␤ and cdk5 is not necessary to obtain hyperphosphorylated tau in vivo, and indicate that inhibition of PP2A is likely the dominant factor in inducing tau hyperphosphorylation in the starved mouse, overriding the inhibition of key tau kinases such as TPKI/GSK3␤ and cdk5. Furthermore, these data give strong support to the hypothesis that PP2A is important for the regulation of tau phosphorylation in the adult brain, and provide in vivo evidence in support of a central role of PP2A in tau hyperphosphorylation in AD. Alzheimer's disease (AD)1 is a neurodegenerative disorder characterized by the presence of two histopathological hallmarks called senile plaques and neurofibrillary tangles. The former are deposits of the ␤-amyloid peptide (A␤) (1), whereas neurofibrillary tangles consist of hyperphosphorylated tau protein assembled in paired helical filaments (PHF) (2). Hyperphosphorylation refers to the state that tau is phosphorylated at more sites than tau from adult brain and that, for a given site, a higher than normal percentage of tau molecules is phosphorylated (3). Tau is a microtubule-associated protein, and its normal physiological function is to bind and stabilize microtubules. In vitro studies have shown that PHF-tau fails to promote microtubule assembly (4 -9), and thus it has been proposed to lead to microtubule destabilization, appearance of neurofibrillary tangles, and neurodegeneration in AD brain (10). Phosphorylation of tau can be regulated by many protein kinases and phosphatases in vitro (11-13). These findings, and the changes in kinases and phosphatases observed in AD, suggest that tau hyperphosphorylation in AD brain is likely to be due to an imbalance of the protein phosphorylation and dephosphorylation systems. But to date the mechanism of conversion from normal adult tau to hyperphosphorylated tau, the significance of tau hyperphosphorylation in PHF formation, and its relationship to A␤ deposition remain largely elusive.Tau hyperphosphorylation is a physiological reversible response of the brain to stressful conditions like cold water stress 2 (14), heat-shock (15), or starvation (16). Starvation induces decreases in circulating glucose, insulin, and leptin, and inc...

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“…1-4). As described qualitatively (16), tau undergoes phosphorylation and dephosphorylation, illustrated here by phosphorylation-dependent anti-tau antibody AT8 (Fig. 1, A1 and B1).…”

Section: Starvation Up-regulates Activating Phosphorylation Of Mapk Asupporting

confidence: 57%

mentioning

confidence: 99%

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Inhibition of Protein Phosphatase 2A Overrides Tau Protein Kinase I/Glycogen Synthase Kinase 3β and Cyclin-dependent Kinase 5 Inhibition and Results in Tau Hyperphosphorylation in the Hippocampus of Starved Mouse

Planel¹,

Yasutake

Fujita

et al. 2001

Journal of Biological Chemistry

Self Cite

190

157

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show abstract

“…Previous reports demonstrating that modulations of glucose or insulin levels alter tau antigenicity in neuronal cultures support this hypothesis (Cheng and Mattson, 1992;Hong and Lee, 1997;Lesort et al, 1999). We also reported that starvation, which decreases the amount of circulating glucose and insulin and lowers glucose utilization (Newsholme, 1976;Cherel et al, 1988), induces AD-like tau hyperphosphorylation in mice (Yanagisawa et al, 1999;Planel et al, 2001).…”

Section: Introductionmentioning

confidence: 71%

Alterations in Glucose Metabolism Induce Hypothermia Leading to Tau Hyperphosphorylation through Differential Inhibition of Kinase and Phosphatase Activities: Implications for Alzheimer's Disease

Planel¹,

Miyasaka²,

et al. 2004

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Alzheimer's disease (AD) brains contain neurofibrillary tangles (NFTs) composed of abnormally hyperphosphorylated tau protein.Regional reductions in cerebral glucose metabolism correlating to NFT densities have been reported in AD brains. Assuming that reduced glucose metabolism might cause abnormal tau hyperphosphorylation, we induced in vivo alterations of glucose metabolism in mice by starvation or intraperitoneal injections of either insulin or deoxyglucose. We found that the treatments led to abnormal tau hyperphosphorylation with patterns resembling those in early AD brains and also resulted in hypothermia. Surprisingly, tau hyperphosphorylation could be traced down to a differential effect of low temperatures on kinase and phosphatase activities. These data indicate that abnormal tau hyperphosphorylation is associated with altered glucose metabolism through hypothermia. Our results imply that serine-threonine protein phosphatase 2A plays a major role in regulating tau phosphorylation in the adult brain and provide in vivo evidence for its crucial role in abnormal tau hyperphosphorylation in AD.

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“…For example, in mice hyperphosphorylation of tau protein, a significant step in AD etiology, may be induced by starvation. 11 On the other hand, brain-derived neurotrophic factor, a factor that plays a controlling role in neuroprotection, is increased in the hippocampus and cerebral cortex in rats on a dietary restriction. 12 Given these differing findings, it is of interest to study whether weight change influences the cognitive performance of elderly citizens.…”

Section: Introductionmentioning

confidence: 99%

Weight change and cognitive performance

2004

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METHODS:The predictive power of the annual change in BMI with cognitive performance was investigated by a binary logistic regression analysis (backward) using sex, age, BMI 1990, BMI 2000, diastolic blood pressure, diabetes status, and optimal health status as additional predictors. RESULTS: In the last step, the following variables remained in the model: annual change in BMI (quadratic term; Po0.01); ApoE genotype (Po0.05); and optimal health status (Po0.01). CONCLUSION: The association between the extent of weight change and poorer cognitive performance could be either a consequence of cognitive impairment or an early symptom of neurodegenerative decline.

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Starvation induces tau hyperphosphorylation in mouse brain: implications for Alzheimer's disease

Cited by 114 publications

References 37 publications

Inhibition of Protein Phosphatase 2A Overrides Tau Protein Kinase I/Glycogen Synthase Kinase 3β and Cyclin-dependent Kinase 5 Inhibition and Results in Tau Hyperphosphorylation in the Hippocampus of Starved Mouse

Inhibition of Protein Phosphatase 2A Overrides Tau Protein Kinase I/Glycogen Synthase Kinase 3β and Cyclin-dependent Kinase 5 Inhibition and Results in Tau Hyperphosphorylation in the Hippocampus of Starved Mouse

Alterations in Glucose Metabolism Induce Hypothermia Leading to Tau Hyperphosphorylation through Differential Inhibition of Kinase and Phosphatase Activities: Implications for Alzheimer's Disease

Weight change and cognitive performance

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