Calcium Regulation in Brain Aging and Alzheimer's Diseases - CORE A Supplemental

Grants and Contracts Details


The supplemental studies proposed in this application derive directly from gene microarray and behavioral analyses in the parent grant that have identified cholesterol synthesis and transport pathways in the hippocampus as potential therapeutic targets against cognitive decline in normal aging and incipient Alzheimer's disease (AD). Although cholesterol dysregulation has been previously linked to AD, many questions remain unresolved and almost nothing is known regarding its role in normal aging-related cognitive decline. To validate these targets through direct molecular interventions, we propose a series of cholesterol pathway gene silencing/knockdown studies using interfering RNAs (iRNA) encoded in viral vectors. One set of studies will be conducted in hippocampal cell culture and one set will be conducted in vivo, in an aging rat model, using microsyringe delivery of viral vectors to the hippocampus. Four months after iRNA delivery in vivo, animals will be tested for degree of cognitive impairment, and their brains will be processed for gene microarray and immunohistochemical testing. Extensive bioinformatic analyses will then compare the results against our large databases of aging/AD marker genes and past behavioral data to determine whether knockdown of any cholesterol pathway gene selectively influenced genomic, cognitive or immunohistochemical aging/AD biomarker profiles to an extent much greater than expected by random chance. If so, this will provide strong indication that alterations in cholesterol pathways not only correlate with, but can also regulate the progression of brain and cognitive changes in aging/AD. These will be the first studies manipulating multiple brain cholesterol pathway genes in combination with systematic assessment of brain aging/AD biomarkers. Evidence of modification of these biomarkers by selective gene knockdown will provide important preclinical validation of cholesterol pathway genes as therapeutic targets. Moreover, because gene manipulation in the brain with viral vectors is already being investigated in human studies, results of the proposed studies might have direct implications for clinical trials.
Effective start/end date12/2/988/31/10


  • National Institute on Aging


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