title: Homocysteine induces tau phosphorylation by inactivating protein phosphatase 2A in rat hippocampus.
abstract: 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.
authors.affiliation: Department of Pathology and Pathophysiology, Hubei Provincial Key Laboratory of Neurological Disease, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Chang-E
authors.initials: CE
authors.lastname: Zhang
authors.forename: Qing
authors.initials: Q
authors.lastname: Tian
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: Jun-Hua
authors.initials: JH
authors.lastname: Peng
authors.forename: Gong-Ping
authors.initials: GP
authors.lastname: Liu
authors.forename: Xin-Wen
authors.initials: XW
authors.lastname: Zhou
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
authors.forename: Dao-Wen
authors.initials: DW
authors.lastname: Wang
authors.forename: Jian-Zhi
authors.initials: JZ
authors.lastname: Wang
mesh_terms: 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*
chemical_list: D016875:tau Proteins; D006710:Homocysteine; D054648:Protein Phosphatase 2