Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG014766-03
Application #
6168971
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Snyder, D Stephen
Project Start
1998-08-01
Project End
2001-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
3
Fiscal Year
2000
Total Cost
$271,726
Indirect Cost

  Institution

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

  Publications

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
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
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
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

Showing the most recent 10 out of 16 publications