4.5 Article

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

Journal

NEUROBIOLOGY OF AGING
Volume 29, Issue 11, Pages 1654-1665

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2007.04.015

Keywords

Alzheimer's disease; homocysteine; protein phosphatase 2A; tau; phosphorylation; methylation

Funding

  1. Natural Science Foundation of China [30430270, 30400171, 30471922]
  2. National Major Grant of China [2006CB500703]

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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 MAC. 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. (C) 2007 Elsevier Inc. All rights reserved.

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