Methylation Of PP2A And Tau/APP Phosphorylation

Estelle Sontag, Viyada Nunbhakdi- Craig, Jean-Marie Sontag, Ramon Diaz-Arrastia, Egon Ogris, Sanjana Dayal, Steven R. Lentz, Erland Arning, and Teodoro Bottiglieri



Elevated plasma levels of homocysteine are a risk factor for Alzheimer's disease. Because high homocysteine levels can inhibit methyltransferases, Sontag et al. pursued a trail of posttranslational protein modifications that might link homocysteine to tau and amyloid precursor protein (APP). Here's their rationale. The likelihood of amyloidogenic APP increases with its phosphorylation, a state reversed by protein phosphatase 2A (PP2A), which itself is affected by methylation. Previous studies have also reported downregulation of neuronal PP2A methyltransferase (PPMT) and reduced PP2A methylation in brain tissue from Alzheimer's patients. In neuroblastoma cells, the authors found that S-adenosylhomocysteine reduced PP2A methylation probably by inhibiting PPMT. In these same cells, phosphorylation of tau and APP was enhanced. In mice prone to high homocysteine levels, a high-methionine, low-folate diet also led to increased brain S-adenosylhomocysteine, downregulation of PPMT, reduced PP2A methylation, and enhanced phosphorylation of tau and APP.







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