Protein Phosphatase-2A Stimulates Astrocytes Migration And The Underlying Mechanism

One of the earliest neuropathological changes in Alzheimer disease (AD) is the accumulation of astrocytes at sites ofβ-amyloid (Aβ) deposits, but the cause of this cellular response is unclear. As the activity of protein phosphatase 2A (PP2A) is significantly decreased in the AD brains, we studied the role of PP2A in astrocytes migration. We observed unexpectedly that PP2A activity associated with glial fibrillary acidic protein (GFAP), an astrocyte marker, was significantly upregulated in tg2576 mice, demonstrated by an increased enzyme activity, a decreased demethylation at leucine-309, and a decreased phosphorylation at tyrosine-307 of PP2A. Further studies by using in vitro wound-healing model and transwell assay demonstrated that upregulation of PP2A pharmacologically and genetically could stimulate astrocytes migration. Activation of PP2A promotes actin organization and inhibits p38MAPK, while simultaneous activation of p38MAPK partially abolishes the PP2A-induced astrocytes migration. Our data suggest that activation of astrocytes PP2A in tg2567 mice may stimulate the migration of astrocytes to the amyloid plaques by p38MAPK inhibition, which may represent an adaptive response to the clearance of Aβ. It implies that PP2A deficits observed in AD may cause Aβaccumulation via hindering the astrocytes migration, thus increasing PP2A may be a promising strategy to remove Aβin AD.