Alterations in glucose metabolism induce hypothermia leading to tau hyperphosphorylation through differential inhibition of kinase and phosphatase activities: implications for Alzheimer's disease.
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.
Planel
Emmanuel
E
Laboratory for Alzheimer's Disease, The Institute of Physical and Chemical Research, Wako-shi, Saitama 351-0198, Japan.
Miyasaka
Tomohiro
T
Launey
Thomas
T
Chui
De-Hua
DH
Tanemura
Kentaro
K
Sato
Shinji
S
Murayama
Ohoshi
O
Ishiguro
Koichi
K
Tatebayashi
Yoshitaka
Y
Takashima
Akihiko
A
D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000378:metabolism; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D002531:Cerebellum / Q000378:metabolism; D003847:Deoxyglucose / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D007035:Hypothermia / Q000139:chemically induced / Q000378:metabolism*; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019579:Neocortex / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010770:Phosphotransferases / Q000378:metabolism*; D054648:Protein Phosphatase 2; D013217:Starvation / Q000378:metabolism; D016875:tau Proteins / Q000187:drug effects / Q000378:metabolism*
D001786:Blood Glucose; D007328:Insulin; D016875:tau Proteins; D003847:Deoxyglucose; D010770:Phosphotransferases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D010744:Phosphoric Monoester Hydrolases; D005947:Glucose