Document Detail


Nucleotides released from Aβ₁₋₄₂ -treated microglial cells increase cell migration and Aβ₁₋₄₂ uptake through P2Y₂ receptor activation.
MedLine Citation:
PMID:  22353164     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-03-14
Journal Detail:
Title:  Journal of neurochemistry     Volume:  121     ISSN:  1471-4159     ISO Abbreviation:  J. Neurochem.     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-04-10     Completed Date:  2012-05-21     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  England    
Other Details:
Languages:  eng     Pagination:  228-38     Citation Subset:  IM    
Copyright Information:
Published 2012. This article is a US Government work and is in the public domain in the USA.
Affiliation:
Department of Biochemistry, University of Missouri, Columbia, Missouri, USA.
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / metabolism
Amyloid beta-Peptides / metabolism*,  toxicity*
Animals
Blotting, Western
Cell Movement / drug effects*
Cell Separation
Enzyme-Linked Immunosorbent Assay
Female
Integrin alpha5 / pharmacology
L-Lactate Dehydrogenase / metabolism
Male
Mice
Mice, Inbred C57BL
Microglia / drug effects,  metabolism*
Microscopy, Electron, Transmission
Neurofibrils / metabolism
Nucleotides / metabolism*,  pharmacology*
Peptide Fragments / metabolism*,  toxicity*
Phagocytosis / drug effects
Purinergic P2Y Receptor Agonists*
RNA, Messenger / biosynthesis,  genetics
Real-Time Polymerase Chain Reaction
Receptors, Purinergic P2Y2 / drug effects*
Uridine Triphosphate / pharmacology
rac GTP-Binding Proteins / physiology
src-Family Kinases / physiology
Grant Support
ID/Acronym/Agency:
AG018357/AG/NIA NIH HHS; P01 AG018357-10/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
0/Amyloid beta-Peptides; 0/Integrin alpha5; 0/Nucleotides; 0/Peptide Fragments; 0/Purinergic P2Y Receptor Agonists; 0/RNA, Messenger; 0/Receptors, Purinergic P2Y2; 0/amyloid beta-protein (1-42); 56-65-5/Adenosine Triphosphate; 63-39-8/Uridine Triphosphate; EC 1.1.1.27/L-Lactate Dehydrogenase; EC 2.7.10.2/src-Family Kinases; EC 3.6.5.2/rac GTP-Binding Proteins
Comments/Corrections

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