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Homocysteine induces tau phosphorylation by inactivating protein phosphatase 2A in rat hippocampus
- Source :
-
Neurobiology of Aging . Nov2008, Vol. 29 Issue 11, p1654-1665. 12p. - Publication Year :
- 2008
-
Abstract
- 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]
- Subjects :
- *HOMOCYSTEINE
*SULFUR amino acids
*CHEMICAL reactions
*CHEMICAL processes
Subjects
Details
- Language :
- English
- ISSN :
- 01974580
- Volume :
- 29
- Issue :
- 11
- Database :
- Academic Search Index
- Journal :
- Neurobiology of Aging
- Publication Type :
- Academic Journal
- Accession number :
- 34431606
- Full Text :
- https://doi.org/10.1016/j.neurobiolaging.2007.04.015