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- Title
Nucleotides released from Aβ<sub>1-42</sub>-treated microglial cells increase cell migration and Aβ<sub>1-42</sub> uptake through P2Y<sub>2</sub> receptor activation.
- Authors
Kim, Hye Jung; Ajit, Deepa; Peterson, Troy S.; Wang, Yanfang; Camden, Jean M.; Gibson Wood, W.; Sun, Grace Y.; Erb, Laurie; Petris, Michael; Weisman, Gary A.
- Abstract
J. Neurochem. (2012) 121, 228-238. Abstract Amyloid β-protein (Aβ) deposits in brains of Alzheimer's disease patients generate proinflammatory cytokines and chemokines that recruit microglial cells to phagocytose Aβ. 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 Aβ. Treatment of mouse primary microglial cells with fibrillar (fAβ1-42) and oligomeric (oAβ1-42) Aβ1-42 aggregation solutions caused a rapid release of ATP (maximum after 10 min). Furthermore, fAβ1-42 and oAβ1-42 treatment for 24 h caused an increase in P2Y2R gene expression. Treatment with fAβ1-42 and oAβ1-42 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 Aβ1-42 by microglial cells within 30 min, which reached a maximum within 1 h, but did not increase Aβ1-42 uptake by primary microglial cells isolated from P2Y2R−/− mice. Inhibitors of αv integrins, Src and Rac decreased UTP-induced Aβ1-42 uptake, suggesting that these previously identified components of the P2Y2R signaling pathway play a role in Aβ phagocytosis by microglial cells. Finally, we found that UTP treatment enhances Aβ1-42 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 Aβ clearance and highlight the P2Y2R as a therapeutic target in Alzheimer's disease.
- Subjects
NUCLEOTIDES; CELL migration; MICROGLIA; IMMUNE response; CYTOKINES; ALZHEIMER'S patients
- Publication
Journal of Neurochemistry, 2012, Vol 121, Issue 2, p228
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/j.1471-4159.2012.07700.x