Loss of P2Y2 Nucleotide Receptors Enhances Early Pathology in the TgCRND8 Mouse Model of Alzheimer's Disease
Neuroinflammation is a prominent feature in Alzheimer's disease (AD) and activation of the brain's innate immune system, particularly microglia, has been postulated to both retard and accelerate AD progression. Recent studies indicate that the G protein-coupled P2Y 2 nucleotide receptor (P...
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Published in | Molecular neurobiology Vol. 49; no. 2; pp. 1031 - 1042 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Boston
Springer US
01.04.2014
|
Subjects | |
Online Access | Get full text |
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Summary: | Neuroinflammation is a prominent feature in Alzheimer's disease (AD) and activation of the brain's innate immune system, particularly microglia, has been postulated to both retard and accelerate AD progression. Recent studies indicate that the G protein-coupled P2Y
2
nucleotide receptor (P2Y
2
R) is an important regulator of innate immunity by assisting in the recruitment of monocytes to injured tissue, neutrophils to bacterial infections and eosinophils to allergen-infected lungs. In this study, we investigated the role of the P2Y
2
R in progression of an AD-like phenotype in the TgCRND8 mouse model that expresses Swedish and Indiana mutations in amyloid precursor protein (APP). Our results indicate that
P2Y
2
R
expression is upregulated in TgCRND8 mouse brain within 10 weeks of age and then decreases after 25 weeks of age, as compared to littermate controls expressing low levels of the
P2Y
2
R
. TgCRND8 mice with homozygous
P2Y
2
R
deletion survive less than 5 weeks, whereas mice with heterozygous
P2Y
2
R
deletion survive for 12 weeks, a time point when TgCRND8 mice are fully viable. Heterozygous
P2Y
2
R
deletion in TgCRND8 mice increased β-amyloid (Aβ) plaque load and soluble Aβ
1–42
levels in the cerebral cortex and hippocampus, decreased the expression of the microglial marker CD11b in these brain regions and caused neurological deficits within 10 weeks of age, as compared to age-matched TgCRND8 mice. These findings suggest that the P2Y
2
R is important for the recruitment and activation of microglial cells in the TgCRND8 mouse brain and that the P2Y
2
R may regulate neuroprotective mechanisms through microglia-mediated clearance of Aβ that when lost can accelerate the onset of an AD-like phenotype in the TgCRND8 mouse. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0893-7648 1559-1182 |
DOI: | 10.1007/s12035-013-8577-5 |