The epidemiological data showing NSAIDS reduce risk for AD demands further investigation at the animal model level. One major target of NSAIDs is Cox-2. Pasinetti and others have found that neuronal COX-2 is elevated in experimental neurodegeneration and in AD brain and that overexpression of Cox-2 potentiates Abeta-mediated oxidative stress in vitro. Based on this and other data, they propose to:
Aim 1. Study the role of Cox-2 in neurodegeneration using experimental Abeta and kainic acid damage in transgenic mice with neuronal, human C0X-2 (NHC) overexpression and in COX-2 knockout mice. They hypothesize COX-2 overexpression will increase neurodegeneration.
Aim 2. To identify the role of COX-2 in primary cultures of NHC transgenic and COX-2 KO mice in the response to Abeta and glutamate neurotoxicity evaluated by MTT and neuronal counts. This parallels aim 1.
Aim 3. To identify mechanisms involved in COX-2-mediated potentiation of Abeta toxicity using organotypic hippocampal slice cultures derived from NHC transgenic and COX-2 KO mice. The hypothesis that COX-2 overexpression amplifies free radical mediated DCF fluorescence and lipid peroxidation will be tested.
Aim 4. To study the role of COX-2 overexpression in bigenic NHC X APPsw (Hsiao mice) which are hypothesized to have accelerated neurodegeneration and cognitive impairment.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG014766-02
Application #
6043090
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1998-08-01
Project End
2001-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Psychiatry
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029
Qin, Weiping; Haroutunian, Vahram; Katsel, Pavel et al. (2009) PGC-1alpha expression decreases in the Alzheimer disease brain as a function of dementia. Arch Neurol 66:352-61
Qin, Weiping; Zhao, Wei; Ho, Lap et al. (2008) Regulation of forkhead transcription factor FoxO3a contributes to calorie restriction-induced prevention of Alzheimer's disease-type amyloid neuropathology and spatial memory deterioration. Ann N Y Acad Sci 1147:335-47
Mukherjee, Piali; Thomas, Sunil; Pasinetti, Giulio Maria (2008) Complement anaphylatoxin C5a neuroprotects through regulation of glutamate receptor subunit 2 in vitro and in vivo. J Neuroinflammation 5:5
Zhao, Zhong; Xiang, Zhongmin; Haroutunian, Vahram et al. (2007) Insulin degrading enzyme activity selectively decreases in the hippocampal formation of cases at high risk to develop Alzheimer's disease. Neurobiol Aging 28:824-30
Pasinetti, Giulio Maria; Zhao, Zhong; Qin, Weiping et al. (2007) Caloric intake and Alzheimer's disease. Experimental approaches and therapeutic implications. Interdiscip Top Gerontol 35:159-75
Ho, Lap; Qin, Weiping; Stetka, Breton S et al. (2006) Is there a future for cyclo-oxygenase inhibitors in Alzheimer's disease? CNS Drugs 20:85-98
Xiang, Zhongmin; Haroutunian, Vahram; Ho, Lap et al. (2006) Microglia activation in the brain as inflammatory biomarker of Alzheimer's disease neuropathology and clinical dementia. Dis Markers 22:95-102
Pasinetti, Giulio Maria; Ho, Lap; Pompl, Patrick (2002) Amyloid immunization in Alzheimer's disease: do we promote amyloid scavenging at the cost of inflammatory degeneration? Neurobiol Aging 23:665-6
Butterfield, D Allan; Griffin, Sue; Munch, Gerald et al. (2002) Amyloid beta-peptide and amyloid pathology are central to the oxidative stress and inflammatory cascades under which Alzheimer's disease brain exists. J Alzheimers Dis 4:193-201
Mirjany, Mana; Ho, Lap; Pasinetti, Giulio Maria (2002) Role of cyclooxygenase-2 in neuronal cell cycle activity and glutamate-mediated excitotoxicity. J Pharmacol Exp Ther 301:494-500

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