Nucleotides released from Aβ 1-42-treated microglial cells increase cell migration and Aβ 1-42 uptake through P2Y 2 receptor activation

Hye Jung Kim, Deepa Ajit, Troy S. Peterson, Yanfang Wang, Jean M. Camden, W. Gibson Wood, Grace Y. Sun, Laurie Erb, Michael Petris, Gary A. Weisman

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

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 2receptors (P2Y 2Rs) in macrophages to promote clearance of dead cells. In this study, we investigated the role of P2Y 2Rs 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 2R 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 2R 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 2R -/- 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 2R 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 2R -/- mice. Taken together, our findings suggest that P2Y 2Rs can activate microglial cells to enhance Aβ clearance and highlight the P2Y 2R as a therapeutic target in Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)228-238
Number of pages11
JournalJournal of Neurochemistry
Volume121
Issue number2
DOIs
StatePublished - Apr 2012

Keywords

  • Alzheimer's disease
  • Microglia
  • Migration
  • Nucleotide
  • P2y receptor
  • β-amyloid phagocytosis

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this