Research in our lab is focused on the role of the gene Apolipoprotein E (APOE) in modulating cerebral metabolism and Alzheimer's Disease pathogenesis. In humans, the APOE gene exists in three common alleles: E2, E3 and E4. The E4 allele of APOE dramatically increases AD risk (up to 15-fold). Conversely, the E2 allele is associated with a substantial reduction in risk and increased longevity.
Our studies aim to understand early-life changes in metabolism associated with APOE and include a special focus on glia and their contributions to neurodegeneration. Our lab's overarching goal is to identify therapeutic targets that will allow us to reprogram metabolism in individuals at-risk for Alzheimer's Disease in order to enhance cognitive resilience and to extend the brain’s health span.
Our studies aim to understand early-life changes in metabolism associated with APOE and include a special focus on glia and their contributions to neurodegeneration. Our lab's overarching goal is to identify therapeutic targets that will allow us to reprogram metabolism in individuals at-risk for Alzheimer's Disease in order to enhance cognitive resilience and to extend the brain’s health span.
APOE and the PPP: Glucose Metabolism and Oxidative Stress in Alzheimer's Disease.
The central hypothesis of this project is that APOE influences neuronal function and survival through isoform-specific changes in glucose metabolism. Specifically, we hypothesize that E4 impairs cognition through metabolic reprogramming in which glucose uptake is decreased and redox management via the pentose phosphate pathway (PPP) is reduced. To test our hypothesis, we are employging a unique ‘omics approach to test a novel mechanism which potentially ties E4 to neuropathological changes in cerebral glucose metabolism, oxidative stress and neuronal survival.
APOE and cerebral energy substrate balance in aging and Alzheimer's Disease
Glucose competes with fatty acids for oxidation through a biochemical mechanism known as the Randle cycle. Early research from our lab suggest that E2 mice show a marked shift in preference toward glucose oxidation, and away from fatty acid β-oxidation. While the brain does β-oxidize a meaningful amount of fatty acids, it is thought that high rates of cerebral β-oxidation lead to neuronal dysfunction. The central hypothesis of this project is that the APOE isoforms differentially shift the Randle cycle balance: E2 in favor of glucose, E4 in favor of fatty acids. To test our hypothesis, we are currently: i) leveraging human APOE mouse models and cell lines to determine the rates of uptake and oxidation of various energy substrates at tissue and cell-specific levels, ii) combining transcriptomics with state-of-the-art “tracer metabolomics” to probe both the level at which E2 exerts its effects on metabolic networks, and iii) measuring basal metabolic rates and respiratory exchange ratios in young, cognitively normal individuals of known APOE genotype.
Lipid Droplets, APOE and Alzheimer's Disease
Interestingly, one of Dr. Alois Alzheimer's original findings in 1907 was that glial cells contained "adipose saccules". Many now think he was referring to lipid droplets - intracellular stores of lipid. Does APOE (itself a lipid associated protein) have a role to play in the formation of lipid droplets in the Alzheimer's brain? Our lab is attempting to answer that question using a combination of in vitro, in vivo and ex vivo approaches to probe the role of APOE in modulating lipid metabolism and droplet biology.
Our lab is supported by generous funding from the following:
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