Epidemiological evidence suggests that ongoing mental or physical activity may attenuate the cognitive decline of Alzheimer's disease, or delay its onset. However, there are conflicting studies that do not show a benefit for increased cognitive activity or exercise for Alzheimer's patients. In addition, an alternate hypothesis suggests that some patients are predisposed to get Alzheimer's disease by early adulthood, and do not have the cognitive capacity or inclination to engage in mentally stimulating activity. The experiments proposed in this proposal are designed to establish cause-and-effect relationships between ongoing mental or physical activity and cognitive status in transgenic mice bearing the Swedish mutation of the amyloid precursor protein (APP). These transgenic mice develop Alzheimer-like amyloid plaques starting at approximately 10 months of age. When fed a folate-deficient diet supplemented with homocysteine for 3 months, APP transgenic mice, but not wild-type control mice, develop hippocampal-specific cell death. Thus we will be able to determine not only whether increased physical or mental activity improves cognitive performance but also whether it affects the rate of cell death or amyloid plaque formation, information that is not obtainable in human Alzheimer patients. Together, the data provided by the proposed experiments will inform us as to the potential effectiveness of cognitively stimulating activities or physical exercise as therapeutic or preventative measures in the fight against Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG022439-01
Application #
6672745
Study Section
Biobehavioral and Behavioral Processes 3 (BBBP)
Program Officer
Snyder, Stephen D
Project Start
2003-09-01
Project End
2007-07-31
Budget Start
2003-09-01
Budget End
2004-07-31
Support Year
1
Fiscal Year
2003
Total Cost
$295,960
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Rao, Shailaja Kishan; Ross, Jordan M; Harrison, Fiona E et al. (2015) Differential proteomic and behavioral effects of long-term voluntary exercise in wild-type and APP-overexpressing transgenics. Neurobiol Dis 78:45-55
Harrison, F E; May, J M; McDonald, M P (2010) Vitamin C deficiency increases basal exploratory activity but decreases scopolamine-induced activity in APP/PSEN1 transgenic mice. Pharmacol Biochem Behav 94:543-52
Bernardo, Alexandra; Harrison, Fiona E; McCord, Meghan et al. (2009) Elimination of GD3 synthase improves memory and reduces amyloid-beta plaque load in transgenic mice. Neurobiol Aging 30:1777-91
Harrison, F E; Hosseini, A H; McDonald, M P (2009) Endogenous anxiety and stress responses in water maze and Barnes maze spatial memory tasks. Behav Brain Res 198:247-51
Harrison, F E; Hosseini, A H; McDonald, M P et al. (2009) Vitamin C reduces spatial learning deficits in middle-aged and very old APP/PSEN1 transgenic and wild-type mice. Pharmacol Biochem Behav 93:443-50
Harrison, F E; Allard, J; Bixler, R et al. (2009) Antioxidants and cognitive training interact to affect oxidative stress and memory in APP/PSEN1 mice. Nutr Neurosci 12:203-18
Harrison, Fiona E; Yu, Sarah S; Van Den Bossche, Kristen L et al. (2008) Elevated oxidative stress and sensorimotor deficits but normal cognition in mice that cannot synthesize ascorbic acid. J Neurochem 106:1198-208
Ariga, Toshio; McDonald, Michael P; Yu, Robert K (2008) Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease--a review. J Lipid Res 49:1157-75
Bernardo, Alexandra; McCord, Meghan; Troen, Aron M et al. (2007) Impaired spatial memory in APP-overexpressing mice on a homocysteinemia-inducing diet. Neurobiol Aging 28:1195-205
Reiserer, R S; Harrison, F E; Syverud, D C et al. (2007) Impaired spatial learning in the APPSwe + PSEN1DeltaE9 bigenic mouse model of Alzheimer's disease. Genes Brain Behav 6:54-65

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