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 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.