Details

Autor(en) / Beteiligte

• Zhang, Chang-E
• Tian, Qing
• Wei, Wei
• Peng, Jun-Hua
• Liu, Gong-Ping
• Zhou, Xin-Wen
• Wang, Qun
• Wang, Dao-Wen
• Wang, Jian-Zhi

Titel

Homocysteine induces tau phosphorylation by inactivating protein phosphatase 2A in rat hippocampus

Ist Teil von

• Neurobiology of aging, 2008-11, Vol.29 (11), p.1654-1665

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2008

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 Leu309 -demethylation and Tyr307 -phosphorylation of PP2A catalytic subunit (PP2AC ). PP2AC Leu309 -demethylation was positively correlated with its Tyr307 -phosphorylation; and the abnormally modified PP2AC was incompetent in binding to its regulatory subunit (PP2AB ). Homocysteine also activated methylesterase which stimulates demethylation of PP2AC . In hippocampal slices of the homocysteine injected-rats and of the AD patients, the demethylated but not the methylated PP2AC 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 PP2AC . These results suggest that homocysteine may be an upstream effector to induce AD-like tau hyperphosphorylation through inactivating PP2A.