During the past five years a canine model of aging has been evaluated, with emphasis on categorization of cognitive decline and links with neuropathology. We have demonstrated that aged canines show a decline in memory and learning and a corresponding increase in brain pathology. We specifically propose that working memory, and learning that involves abstract rules and requires flexibility, are particularly sensitive to age. These age sensitive functions are likely to depend on cortical circuits that converge in the prefrontal cortex. We further hypothesize that age-related impairment is partially attributable to oxidative stress that begins in middle age and triggers a cascade of events resulting in both accumulation of neurotoxic substances, such as beta-amyloid (A beta) protein and possibly cell dysfunction or death. The present proposal seeks first to extend our evaluation of the canine model and establish the cognitive processes that are particularly sensitive to aging, using both cross sectional and longitudinal strategies. Second, we propose to analyze key endpoints in an oxidative stress cascade that may be part of a sequence of neuropathological events underlying age-related impairment. Third, as a test of theory, we will use an intervention study to modify oxidative stress levels in dogs. Thus, this proposal incorporates a new component, to test the cognitive and neurobiological effects of intervention with a diet rich in a broad spectrum of antioxidants. This component of the proposal incorporates both a short-term (cross-sectional) and a long-term (longitudinal study) of cognition and brain aging in the dog. Specifically, direct measures of protein, lipid and DNA/RNA oxidation will be examined in control and treated animals along with hypothesized downstream consequences of oxidation serving as indirect measures, e.g., increased A beta, increased DNA strand breaks, caspase levels/activation and altered synaptic density. Overall, this project should provide unique insight into the role of oxidative damage and subsequent molecular cascades on the progression of brain aging and cognitive decline.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG012694-07
Application #
6372030
Study Section
Special Emphasis Panel (ZRG1-IFCN-7 (01))
Program Officer
Wagster, Molly V
Project Start
1995-09-30
Project End
2005-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
7
Fiscal Year
2001
Total Cost
$423,131
Indirect Cost
Name
University of California Irvine
Department
Neurology
Type
Schools of Medicine
DUNS #
161202122
City
Irvine
State
CA
Country
United States
Zip Code
92697
Snigdha, Shikha; Yassa, Michael A; deRivera, Christina et al. (2017) Pattern separation and goal-directed behavior in the aged canine. Learn Mem 24:123-131
Snigdha, Shikha; Prieto, G Aleph; Petrosyan, Arpine et al. (2016) H3K9me3 Inhibition Improves Memory, Promotes Spine Formation, and Increases BDNF Levels in the Aged Hippocampus. J Neurosci 36:3611-22
Snigdha, Shikha; de Rivera, Christina; Milgram, Norton W et al. (2016) Effect of mitochondrial cofactors and antioxidants supplementation on cognition in the aged canine. Neurobiol Aging 37:171-178
Snigdha, Shikha; Milgram, Norton W; Willis, Sherry L et al. (2013) A preclinical cognitive test battery to parallel the National Institute of Health Toolbox in humans: bridging the translational gap. Neurobiol Aging 34:1891-901
Snigdha, Shikha; Smith, Erica D; Prieto, G Aleph et al. (2012) Caspase-3 activation as a bifurcation point between plasticity and cell death. Neurosci Bull 28:14-24
Dowling, Amy L S; Head, Elizabeth (2012) Antioxidants in the canine model of human aging. Biochim Biophys Acta 1822:685-9
Fahnestock, Margaret; Marchese, Monica; Head, Elizabeth et al. (2012) BDNF increases with behavioral enrichment and an antioxidant diet in the aged dog. Neurobiol Aging 33:546-54
Snigdha, Shikha; Christie, Lori-Ann; De Rivera, Christina et al. (2012) Age and distraction are determinants of performance on a novel visual search task in aged Beagle dogs. Age (Dordr) 34:67-73
Pop, Viorela; Head, Elizabeth; Berchtold, Nicole C et al. (2012) A? aggregation profiles and shifts in APP processing favor amyloidogenesis in canines. Neurobiol Aging 33:108-20
Snigdha, Shikha; Berchtold, Nicole; Astarita, Giuseppe et al. (2011) Dietary and behavioral interventions protect against age related activation of caspase cascades in the canine brain. PLoS One 6:e24652

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