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Nucleotides released from Aβ 1–42 ‐treated microglial cells increase cell migration and Aβ 1–42 uptake through P2Y 2 receptor activation
Author(s) -
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.
Publication year - 2012
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2012.07700.x
Subject(s) - apyrase , microglia , p2y receptor , phagocytosis , receptor , proinflammatory cytokine , microbiology and biotechnology , chemistry , chemokine , biology , biochemistry , purinergic receptor , inflammation , immunology
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 P2Y 2 receptors (P2Y 2 Rs) in macrophages to promote clearance of dead cells. In this study, we investigated the role of P2Y 2 Rs in the phagocytosis and clearance of Aβ. Treatment of mouse primary microglial cells with fibrillar (fAβ 1–42 ) and oligomeric (oAβ 1–42 ) Aβ 1–42 aggregation solutions caused a rapid release of ATP (maximum after 10 min). Furthermore, fAβ 1–42 and oAβ 1–42 treatment for 24 h caused an increase in P2Y 2 R gene expression. Treatment with fAβ 1–42 and oAβ 1–42 aggregation solutions increased the motility of neighboring microglial cells, a response inhibited by pre‐treatment with apyrase, an enzyme that hydrolyzes nucleotides. The P2Y 2 R agonists ATP and UTP caused significant uptake of Aβ 1–42 by microglial cells within 30 min, which reached a maximum within 1 h, but did not increase Aβ 1–42 uptake by primary microglial cells isolated from P2Y 2 R −/− mice. Inhibitors of α v integrins, Src and Rac decreased UTP‐induced Aβ 1–42 uptake, suggesting that these previously identified components of the P2Y 2 R signaling pathway play a role in Aβ phagocytosis by microglial cells. Finally, we found that UTP treatment enhances Aβ 1–42 degradation by microglial cells, but not in cells isolated from P2Y 2 R −/− mice. Taken together, our findings suggest that P2Y 2 Rs can activate microglial cells to enhance Aβ clearance and highlight the P2Y 2 R as a therapeutic target in Alzheimer’s disease.