The major goal of this Program Project Grant (PPG) is to explore novel and under-studied pathways that contribute to Alzheimer's disease (AD). The decreased neuronal plasticity and cognitive memory loss found in people with AD is associated with chronic oxidative stress and increased production of neurotoxic oligomeric amyloid beta (A?) that cause release of cytokines and other molecules that promote neurodegeneration and chronic inflammation. We believe that devising methods to limit chronic effects of oxidative stress and oligomeric A? production would have profoundly positive consequences for AD patients. Based on promising results in the current grant period, we propose to better understand the mechanisms underlying the effects of oxidative stress and A? in neurons and glial cells, information that will lead to better treatments for prevention of neurodegeneration and chronic inflammation in the AD brain. We will investigate neuroprotective and pro-inflammatory pathways in neurons, glia and brain microvessels using cell and animal models of AD. Three projects will test the hypotheses that: (1) progression of AD involves expression and activation of the cPLA?/sPLA2/NADPH oxidase pathways to induce inflammatory responses in glial cells and impairment of neuronal functions;(2) chronic inflammation in AD is mediated by P2Y2 receptors (P2Y2Rs) for cytokine-like nucleotides in astrocytes and cerebral microvessels through transactivation of integrins and growth factor receptors, and P2Y2Rs mediate neuroprotective APP processing by a different pathway than inflammation;and (3) statins have both cholesterol-independent and -dependent mechanisms of action that are neuroprotective due to drug-induced transcriptional up-regulation of anti-apoptotic Bcl-2 by ET- 1/calcinurin/NFAT-dependent pathways and inhibition of Rac1 geranylgeranylation. Two cores will support the projects: (A) Administrative Core A will oversee progress on the PPG;(B) Cell, Molecular, and Animal Core B will provide standardized preparations of primary cell cultures and transfectants, and transgenic mice, prepare tissue sections, and perform immunohistochemical analyses, Laser Capture Microdissection, microarray screening of gene expression, and molecular biology assays. These collaborative studies should identify novel strategies to control chronic inflammation and neurodegeneration in AD.

Public Health Relevance

Dementia is a brain disorder that seriously affects a person's ability to carry out daily activities. The most common form of dementia among older people is Alzheimer's disease (AD), which initially involves the parts of the brain that control thought, memory, and language. Up to 4.5 million Americans suffer from AD from which there is no cure.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
3P01AG018357-10S1
Application #
8530657
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4 (O3))
Program Officer
Petanceska, Suzana
Project Start
2001-05-01
Project End
2014-04-30
Budget Start
2012-09-01
Budget End
2014-04-30
Support Year
10
Fiscal Year
2012
Total Cost
$124,111
Indirect Cost
$25,873
Name
University of Missouri-Columbia
Department
Biochemistry
Type
Schools of Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Yang, X; Sheng, W; Ridgley, D M et al. (2015) Astrocytes regulate α-secretase-cleaved soluble amyloid precursor protein secretion in neuronal cells: Involvement of group IIA secretory phospholipase A2. Neuroscience 300:508-17
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
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
Wood, W Gibson; Mΰller, Walter E; Eckert, Gunter P (2014) Statins and neuroprotection: basic pharmacology needed. Mol Neurobiol 50:214-20
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
Wood, W Gibson; Li, Ling; Muller, Walter E et al. (2014) Cholesterol as a causative factor in Alzheimer's disease: a debatable hypothesis. J Neurochem 129:559-72
Ajit, Deepa; Woods, Lucas T; Camden, Jean M et al. (2014) Loss of P2Yýýý nucleotide receptors enhances early pathology in the TgCRND8 mouse model of Alzheimer's disease. Mol Neurobiol 49:1031-42
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

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