Our research focuses on the effects of genetic and environmental factors on cerebral metabolism and Alzheimer’s disease (AD) risk. Specifically, our lab is devoted to exploring the metabolic effects of the E4 isoform of apolipoprotein E (APOE), the strongest genetic risk factor for late onset AD.
To do this, we have embraced a translational approach: we combine in vitro measures of cellular metabolism with innovative ex vivo and in vivo tracer metabolomics techniques and multiphoton imaging. We have also initiated a clinical research study in which we are studying the metabolic effects of APOE, and have plans to continue growing this sector of our research program. While rooted in neuroscience, our work is translational, cross-disciplinary and has strong vascular and metabolic components. Our end goal is to identify novel nutritional and therapeutic targets for high risk E4+ carriers (~1 out of 5 individuals), and to translate these findings into new approaches to delay or prevent Alzheimer's disease.
To do this, we have embraced a translational approach: we combine in vitro measures of cellular metabolism with innovative ex vivo and in vivo tracer metabolomics techniques and multiphoton imaging. We have also initiated a clinical research study in which we are studying the metabolic effects of APOE, and have plans to continue growing this sector of our research program. While rooted in neuroscience, our work is translational, cross-disciplinary and has strong vascular and metabolic components. Our end goal is to identify novel nutritional and therapeutic targets for high risk E4+ carriers (~1 out of 5 individuals), and to translate these findings into new approaches to delay or prevent Alzheimer's disease.
Our research program is currently organized into primary focus areas as follows:
Focus Area 1. APOE and the PPP: Glucose Metabolism and Oxidative Stress in Alzheimer's Disease.
(funded by R01 AG060056) (preliminary work funded by NIH Common Fund Metabolomics Program)
The central hypothesis of this research 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. We base this idea on the following points: 1) E4 carriers have an increased risk of AD, while E2 carriers are protected. 2) Individuals with AD show a consistent pattern of cerebral glucose hypometabolism. 3) Even young, cognitively normal E4 carriers show a similar pattern of hypometabolism. 4) Neurons and astrocytes predominantly metabolize glucose, a significant amount of which is shunted to the PPP. 5) The PPP generates reducing factors such as glutathione, and decreased PPP activity leads to oxidative stress and cell death. 6) Our novel and compelling preliminary data describe an E4-associated decrease in glucose metabolism and document reductions in multiple PPP metabolites. 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.
Focus Area 1. APOE and the PPP: Glucose Metabolism and Oxidative Stress in Alzheimer's Disease.
(funded by R01 AG060056) (preliminary work funded by NIH Common Fund Metabolomics Program)
The central hypothesis of this research 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. We base this idea on the following points: 1) E4 carriers have an increased risk of AD, while E2 carriers are protected. 2) Individuals with AD show a consistent pattern of cerebral glucose hypometabolism. 3) Even young, cognitively normal E4 carriers show a similar pattern of hypometabolism. 4) Neurons and astrocytes predominantly metabolize glucose, a significant amount of which is shunted to the PPP. 5) The PPP generates reducing factors such as glutathione, and decreased PPP activity leads to oxidative stress and cell death. 6) Our novel and compelling preliminary data describe an E4-associated decrease in glucose metabolism and document reductions in multiple PPP metabolites. 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.
Focus Area 2. ApoE and cerebral energy substrate balance in aging and AD.
(pending funding - R01 AG062550) (preliminary work funded by NIGMS COBRE program)
Glucose competes with fatty acids (FA) for oxidation through a biochemical mechanism known as the Randle cycle. Our preliminary data suggest that the apoE isoforms differentially alter this glucose/FA balance in both the brain and periphery. Exciting preliminary data from our lab suggest that E2 mice show a marked shift in preference toward glucose oxidation, and away from FA β-oxidation. While the brain does β-oxidize a meaningful amount of FA, it is thought that high rates of cerebral β-oxidation lead to neuronal dysfunction. Our preliminary data suggest that E2 astrocytes have increased rates of glucose uptake and oxidation. Conversely, E4 astrocytes show a higher degree of FA uptake and oxidation. Thus, 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 FA. Specifically, we hypothesize that E2 exerts neuroprotective effects via a metabolic preference for glucose utilization. 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 trancriptomics 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 APOE genotyped individuals.
Our lab is supported by generous funding from the following:
