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 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. [Copyright &y& Elsevier]