Upregulation of astrocytes protein phosphatase-2A stimulates astrocytes migration via inhibiting p38 MAPK in tg2576 mice.
One of the earliest neuropathological changes in Alzheimer disease (AD) is the accumulation of astrocytes at sites of β-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, an astrocyte marker, was significantly upregulated in tg2576 mice, demonstrated by an increased enzyme activity, a decreased demethylation at leucine-309 (DM-PP2Ac), and a decreased phosphorylation at tyrosine-307 of PP2A (pY307-PP2Ac). 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 p38 mitogen-activated protein kinases (p38 MAPK), while simultaneous activation of p38 MAPK 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 p38 MAPK inhibition, implying that PP2A deficits observed in AD may cause Aβ accumulation via hindering the astrocytes migration.
Pathophysiology Department, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, HuBei, People's Republic of China.
Xiu-Ping
XP
Liu
Hong-Yun
HY
Zheng
Min
M
Qu
Yao
Y
Zhang
Fu-Yuan
FY
Cao
Qun
Q
Wang
Dan
D
Ke
Gong-Ping
GP
Liu
Jian-Zhi
JZ
Wang
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
D048051:p38 Mitogen-Activated Protein Kinases; D054648:Protein Phosphatase 2