Chronic inflammation, a major contributor to neurodegeneration in AD, occurs when glial cells (i.e., astrocytes and microglia) undergo prolonged activation in response to oxidative stress. Oxidative stress and neurotoxic oligomeric p-amyloid (Ap) peptide production in AD brain can increase extracellular levels of cytokines and nucleotides that activate receptors in glial cells to stimulate intracellular signaling pathways and promote reactive gliosis, an underlying cause of neuroinflammation. Chronic inflammation can be exacerbated by the infiltration of blood monocytes across the endothelium of cerebral microvessels that maintain the blood-brain barrier. Our research has shown that a G protein-coupled P2Y2 nucleotide receptor (P2Y2R) expressed in astrocytes and vascular cells is activated by the extracellular nucleotides ATP and DTP to induce responses characteristic of reactive gliosis and vascular inflammation. The P2Y2R is distinguished among G protein-coupled receptors in its ability to interact directly with integrins (e.g., avPa/ps) and growth factor receptors to transactivate their signal transduction pathways. Proposed studies will test the hypothesis that chronic inflammation caused by oxidative stress and oligomeric Ap production in AD brain is mediated by P2Y2Rs for cytokine-like nucleotides in astrocytes and cerebromicrovessels through transactivation of integrins and growth factor receptors. P2Y2Rs also activate a-secretase to promote neuroprotective APP processing by distinct pathways from inflammation, suggesting that this divergence in P2Y2R signaling can be exploited to retard the development of AD. Studies will evaluate three specific aims.
Aim 1 will elucidate pro-inflammatory pathways coupled to P2Y2Rs andATP release and the effects of oxidative stress and oligomeric Ap42 in primary astrocytes from TgCRNDS mice that harbor the Swedish (K670M/N671L) and Indiana (V717F) mutations in APP, an accepted animal model of AD, as compared to C57/BL6 (wild type), P2Y2R'/"""""""", and TgCRNDS x P2Y2R~'~ mice. Studies also will determine mechanisms of transcriptional regulation of the P2Y2R.
Aim 2 will determine whether expression of P2Y2Rs, and markers of inflammation and the AD phenotype are up-regulated in astrocytes, neurons and microvessels isolated from brain sections of TgCRNDS mice as compared to C57/BL6, P2Y2R""""""""/"""""""", and TgCRNDS x P2Y2R~'~mice, and quantify ATP release in brain sections.
Aim 3 will determine mechanisms underlying P2Y2R-mediated APP processing in NT-2 cells expressing the Swedish and Indiana double mutant of APP, an in vitro neuronal cell model for AD, and in primary neurons. Together, these studies will provide conclusive evidence to support a role for P2Y2Rs in the pathophysiology of AD, and define novel pathways activated by nucleotides that will lead to better treatments for this debilitating disease.
|Simonyi, Agnes; Chen, Zihong; Jiang, Jinghua et al. (2015) Inhibition of microglial activation by elderberry extracts and its phenolic components. Life Sci 128:30-8|
|Erb, Laurie; Cao, Chen; Ajit, Deepa et al. (2015) P2Y receptors in Alzheimer's disease. Biol Cell 107:1-21|
|Yang, X; Sheng, W; Ridgley, D M et al. (2015) Astrocytes regulate ?-secretase-cleaved soluble amyloid precursor protein secretion in neuronal cells: Involvement of group IIA secretory phospholipase A2. Neuroscience 300:508-17|
|Walker, Jennifer M; Klakotskaia, Diana; Ajit, Deepa et al. (2015) Beneficial effects of dietary EGCG and voluntary exercise on behavior in an Alzheimer's disease mouse model. J Alzheimers Dis 44:561-72|
|Sun, Grace Y; Chuang, Dennis Y; Zong, Yijia et al. (2014) Role of cytosolic phospholipase A2 in oxidative and inflammatory signaling pathways in different cell types in the central nervous system. Mol Neurobiol 50:6-14|
|Afshordel, Sarah; Wood, Wellington Gibson; Igbavboa, Urule et al. (2014) Impaired geranylgeranyltransferase-I regulation reduces membrane-associated Rho protein levels in aged mouse brain. J Neurochem 129:732-42|
|Liao, Zhongji; Cao, Chen; Wang, Jianjie et al. (2014) The P2Y2 Receptor Interacts with VE-Cadherin and VEGF Receptor-2 to Regulate Rac1 Activity in Endothelial Cells. J Biomed Sci Eng 7:1105-1121|
|Ajit, Deepa; Woods, Lucas T; Camden, Jean M et al. (2014) Loss of P2Y? nucleotide receptors enhances early pathology in the TgCRND8 mouse model of Alzheimer's disease. Mol Neurobiol 49:1031-42|
|Wood, W Gibson; Li, Ling; Müller, Walter E et al. (2014) Cholesterol as a causative factor in Alzheimer's disease: a debatable hypothesis. J Neurochem 129:559-72|
|Wood, W Gibson; Igbavboa, Urule; Muller, Walter E et al. (2013) Statins, Bcl-2, and apoptosis: cell death or cell protection? Mol Neurobiol 48:308-14|
Showing the most recent 10 out of 113 publications