The mission of our Perimenopause in Brain Aging and Alzheimer's Disease Program Project is to discover the biological transformations that occur in the brain during the perimenopausal transition that can result in phenotypes predictive of risk for development of AD pathology. The mission of Project 1 is to determine the perimenopausal bioenergetic phenotypes most at risk for developing bioenergetics predictive of AD pathology;delineate the mechanistic pathways involved in development of the at-AD-risk phenotype;and assess the impact of ovarian hormone and nutritional interventions on expression of bioenergetic biomarkers of AD. Utilizing rodent models of human perimenopause. Project 1 will achieve its mission by determining;(1) in Aim 1 the bioenergetic phenotypes induced by the perimenopausal transition, (2) in Aim 2 the mechanisms that generate the at-AD-risk phenotype and (3) in Aim 3 the window of opportunity to prevent bioenergetic at-AD-risk phenotype. To address our hypotheses, we will experimentally determine bioenergetic gene expression across the perimenopausal transition and monitor indicators of mitochondrial function which will include: bioinformatics network analyses of gene expression, in vivo cerebral glucose metabolism and synaptic transmission. Mechanistic analyses will address (1) hypometabolism and cell- specific metabolic profiles, (2) redox control of bioenergetic pathway, and (3) white matter loss. Project 1 collaborates with Projects 2, 3 and 4 to test the hypothesis that decline in brain bioenergetics leads to activation of the inflammatory response in brain (Project 2) which exacerbates mitochondrial function which leads to development of AD pathology (Project 3) and mitochondrial dysfunction is associated with cognitive decline in women assessed through ancillary analyses of the ELITE NIA sponsored clinical trial (Project 4). Outcomes of Project 1 research will include: (1) basic science discovery ofthe bioenergetics ofthe perimenopausal aging transition in brain regions vulnerable to development of AD pathology;(2) mechanistic pathways that lead to decline in bioenergetics in the perimenopausal brain;(3) translational research discovery of the window of opportunity for ovarian hormone intervention to prevent decline in bioenergetics in the perimenopausal brain and (4) clinical associations of bioenergetic gene expression, mitochondrial function in peripheral blood cells and cognitive decline in postmenopausal women.

Public Health Relevance

More than 60% of Alzheimer's disease (AD) patients are women. Project 1 of our Perimenopause Program Project will determine the impact of the perimenopause transition on the ability of the brain to generate the energy required for cognitive function and to prevent development of Alzheimer's. Project 1 research will also determine the window of opportunity for hormone therapy to prevent decline in brain energy to reduce the risk of Alzheimer's.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG026572-09
Application #
8721281
Study Section
Special Emphasis Panel (ZAG1-ZIJ-8)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
9
Fiscal Year
2014
Total Cost
$301,035
Indirect Cost
$118,128
Name
University of Southern California
Department
Type
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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