Homocysteine induces tau phosphorylation by inactivating protein phosphatase 2A in rat hippocampus.
Hyperhomocysteinemia increases the risk of Alzheimer's disease (AD), but the mechanism is elusive. Here, we found that high plasma homocysteine induced by vena caudalis injection for 2 weeks could induce AD-like tau hyperphosphorylation at multiple sites in rat brain hippocampus. Homocysteine inhibited the activity of protein phosphatase 2A (PP2A) with a simultaneously increased Leu(309)-demethylation and Tyr(307)-phosphorylation of PP2A catalytic subunit (PP2A(C)). PP2A(C) Leu(309)-demethylation was positively correlated with its Tyr(307)-phosphorylation; and the abnormally modified PP2A(C) was incompetent in binding to its regulatory subunit (PP2A(B)). Homocysteine also activated methylesterase which stimulates demethylation of PP2A(C). In hippocampal slices of the homocysteine injected-rats and of the AD patients, the demethylated but not the methylated PP2A(C) was co-localized with the hyperphosphorylated tau. A simultaneous supplement of folate and vitamin B12 restored partially the plasma homocysteine level and thus significantly antagonized the homocysteine-induced tau hyperphosphorylation and as well as PP2A inactivation and the activity-related modifications of PP2A(C). These results suggest that homocysteine may be an upstream effector to induce AD-like tau hyperphosphorylation through inactivating PP2A.
Zhang
Chang-E
CE
Department of Pathology and Pathophysiology, Hubei Provincial Key Laboratory of Neurological Disease, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Tian
Qing
Q
Wei
Wei
W
Peng
Jun-Hua
JH
Liu
Gong-Ping
GP
Zhou
Xin-Wen
XW
Wang
Qun
Q
Wang
Dao-Wen
DW
Wang
Jian-Zhi
JZ
D000818:Animals; D004789:Enzyme Activation; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006710:Homocysteine / Q000008:administration & dosage* / Q000097:blood*; D007275:Injections, Intravenous; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D016875:tau Proteins / Q000378:metabolism*
D016875:tau Proteins; D006710:Homocysteine; D054648:Protein Phosphatase 2