Grants and Contracts per year
Grants and Contracts Details
Metabolic dysfunction, as in the case of obesity and insulin resistance (IR), contributes to the development of several age-related diseases, including Alzheimer’s disease (AD). Apolipoprotein E (apoE) is a critical component of circulating lipoproteins found both in the periphery and brain, and the APOE gene encodes three major isoforms in the human population: E2, E3, and E4. E4 is the most significant genetic risk factor for sporadic AD, while E2 is protective. Like obesity and IR, the E4 isoform is also associated with an increased risk of both CVD and dementia, specifically Alzheimer’s disease (AD). Paradoxically, mice and humans with E4 have increased risks for these disorders despite having reduced adiposity, while those with E2 are protected despite increased adiposity. Our preliminary findings in mice suggest that these two factors – obesity and apoE – may be linked by a unifying biological mechanism related to energy substrate preference. Based on our preliminary data, we hypothesize that E4 contributes to cognitive impairment through a metabolic abnormality in which a preference toward fatty acid oxidation results in an inherent inefficiency to utilize glucose. The hypothesis to be tested represents a unifying mechanism by which apoE simultaneously modulates obesity and cognitive function, and has broad implications for the prevention and personalized (genetic) treatment of these disorders. The goals of this proposal are to i) translate our exciting initial findings into human subjects and ii) uncover the precise metabolic pathways that underlie this phenomenon; thereby providing novel biomarkers to predict latent disease and new molecular targets for the prevention or treatment of these disorders. To test the hypothesis that E2 affords neuroprotection by decreasing fatty acid and increasing glucose utilization, we will quantitatively track substrate entry and metabolism through the unique precursor-product “tracing” afforded by Stable Isotope Resolved Metabolomics (SIRM). We will then use a unique multi-omics approach to integrate SIRM results with transcriptomic profiling of human apoE expressing mice and cells in order to identify the specific metabolic pathways altered by E2 expression in both the brain and periphery. Finally, we will translate our findings by measuring respiratory quotient (RQ) in E2-, E3- and E4-expresing individuals at rest, and during a cognitive challenge. Using O2 and CO2 recordings in combination with a measure of urea nitrogen (i.e. protein oxidation), we will calculate RQ, which reflects the ratio of carbohydrate/lipid oxidation, across each trial. Analyzing these data based on status will provide a new understanding of substrate utilization in E2+ individuals, and offer insight into potential apoE effects on peripheral and neural energy responses. If successful, this proposal will provide novel targets by characterizing the neuroprotective metabolic profile of E2 individuals and designing future therapies to mimic these effects. Enhancing cerebral metabolism by making “E2-like” changes to energy balance could have great impact in preventing or delaying the onset of AD.
|Effective start/end date||4/1/19 → 3/31/23|
- National Institute on Aging: $1,785,554.00
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- 1 Finished
Friday Diversity Supplement: Examining the Effects of the Neuroprotective APOE2 Allele on Peripheral Immunometabolism
Johnson, L. & Friday, C.
8/1/21 → 3/31/23
Project: Research project