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The Journal of Neuroscience, March 10, 2004, 24(10):2401-2411; doi:10.1523/JNEUROSCI.5561-03.2004

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

Emmanuel Planel,¹ Tomohiro Miyasaka,¹ Thomas Launey,² De-Hua Chui,¹ Kentaro Tanemura,¹ Shinji Sato,¹ Ohoshi Murayama,³ Koichi Ishiguro,⁴ Yoshitaka Tatebayashi,¹ and Akihiko Takashima¹

¹Laboratory for Alzheimer's Disease and ²Laboratory for Memory and Learning, Brain Science Institute, The Institute of Physical and Chemical Research, Wako-shi, Saitama 351-0198, Japan, ³Laboratory of Molecular Biology, School of Environmental Health Sciences, Azabu University, Sagamihara, Kanagawa 229-8501, Japan, and ⁴Mitsubishi Kagaku Institute of Life Sciences, Machida-shi, Tokyo 195-8511, Japan

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.

Key words: Alzheimer's disease; hypothermia; tau hyperphosphorylation; glucose metabolism; insulin; diabetes mellitus; kinase; serine-threonine protein phosphatase; GSK-3; cdk5; JNK; MAPK

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Received Oct 21, 2003; revised January 15, 2004; accepted January 15, 2004.

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