Nucleotides released from A ss 1-42-treated microglial cells increase cell migration and A ss 1-42 uptake through P2Y2 receptor activationopen access
- Kim, Hye Jung; Ajit, Deepa; Peterson, Troy S.; Wang, Yanfang; Camden, Jean M.; Wood, W. Gibson; Sun, Grace Y.; Erb, Laurie; Petris, Michael; Weisman, Gary A.
- Issue Date
- ss-amyloid phagocytosis; Alzheimer' s disease; microglia; migration; nucleotide; P2Y2 receptor
- JOURNAL OF NEUROCHEMISTRY, v.121, no.2, pp.228 - 238
- Journal Title
- JOURNAL OF NEUROCHEMISTRY
- Start Page
- End Page
- Amyloid beta-protein (A beta) deposits in brains of Alzheimers disease patients generate proinflammatory cytokines and chemokines that recruit microglial cells to phagocytose A beta. Nucleotides released from apoptotic cells activate P2Y2 receptors (P2Y2Rs) in macrophages to promote clearance of dead cells. In this study, we investigated the role of P2Y2Rs in the phagocytosis and clearance of A beta. Treatment of mouse primary microglial cells with fibrillar (fA beta 142) and oligomeric (oA beta 142) A beta 142 aggregation solutions caused a rapid release of ATP (maximum after 10 min). Furthermore, fA beta 142 and oA beta 142 treatment for 24 h caused an increase in P2Y2R gene expression. Treatment with fA beta 142 and oA beta 142 aggregation solutions increased the motility of neighboring microglial cells, a response inhibited by pre-treatment with apyrase, an enzyme that hydrolyzes nucleotides. The P2Y2R agonists ATP and UTP caused significant uptake of A beta 142 by microglial cells within 30 min, which reached a maximum within 1 h, but did not increase A beta 142 uptake by primary microglial cells isolated from P2Y2R-/- mice. Inhibitors of av integrins, Src and Rac decreased UTP-induced A beta 142 uptake, suggesting that these previously identified components of the P2Y2R signaling pathway play a role in A beta phagocytosis by microglial cells. Finally, we found that UTP treatment enhances A beta 142 degradation by microglial cells, but not in cells isolated from P2Y2R-/- mice. Taken together, our findings suggest that P2Y2Rs can activate microglial cells to enhance A beta clearance and highlight the P2Y2R as a therapeutic target in Alzheimers disease.
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- College of Medicine > Department of Medicine > Journal Articles
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