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Loss of P2Y2 Nucleotide Receptors Enhances Early Pathology in the TgCRND8 Mouse Model of Alzheimer's Disease

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Abstract

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 P2Y2 nucleotide receptor (P2Y2R) 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 P2Y2R 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 Aβ1–42 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 P2Y2R is important for the recruitment and activation of microglial cells in the TgCRND8 mouse brain and that the P2Y2R 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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Acknowledgments

This work was supported by NIH grant AG018357.

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Authors and Affiliations

  1. Department of Biochemistry, University of Missouri, 540E Life Sciences Center, 1201 Rollins Road, Columbia, MO, 65211-7310, USA

    Deepa Ajit, Lucas T. Woods, Jean M. Camden, Christina N. Thebeau, Farid G. El-Sayed, Glen W. Greeson, Laurie Erb, Michael J. Petris, Grace Y. Sun & Gary A. Weisman

  2. Interdisciplinary Neurosciences Program, University of Missouri, Columbia, MO, USA

    Laurie Erb, Michael J. Petris, Grace Y. Sun & Gary A. Weisman

  3. Department of Nutritional Sciences and Exercise Physiology, University of Missouri, Columbia, MO, USA

    Michael J. Petris

  4. Department of Pathology and Anatomical Sciences, University of Missouri School of Medicine, Columbia, MO, USA

    Douglas C. Miller

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  1. Deepa Ajit
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Correspondence to Gary A. Weisman.

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Ajit, D., Woods, L.T., Camden, J.M. et al. Loss of P2Y2 Nucleotide Receptors Enhances Early Pathology in the TgCRND8 Mouse Model of Alzheimer's Disease. Mol Neurobiol 49, 1031–1042 (2014). https://doi.org/10.1007/s12035-013-8577-5

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