Grants and Contracts Details
Alzheimer’s disease (AD) is characterized by both changes in metabolism and inflammation. 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. Notably, E4 is associated with both metabolic dysfunction and a heightened pro-inflammatory response. Interestingly, activation of microglia requires a metabolic shift towards increased glycolytic activity and decreased oxidative phosphorylation, a central concept of immunometabolism. Additionally, it is now clear that APOE itself is pivotal to the induction of this phenotypic switch in microglia, driving a neurodegenerative ‘disease associated microglia’ (DAM) transcriptional signature. Our preliminary findings have begun to tie these two phenomenon together, and have prompted our central hypothesis that APOE genotype inherently alters microglial immunometabolism. Specifically, we hypothesize that expression of E4 drives pro-glycolytic flux, pushing microglia toward a neurodegenerative phenotype, and conversely that the neuroprotective E2 isoform drives a pro-oxidative, homeostatic state. To test this hypothesis, we will employ single cell and spatial transcriptomic methods to define APOE effects on the metabolic trajectory of microglia in both a cell type- and brain region-specific manner. We will then use a combination of matrix assisted laser desorption/ionization (MALDI) and desorption electrospray ionization (DESI) mass spectrometry (MS) imaging to profile APOE-associated changes in thousands of distinct lipids and metabolites across the brain and across the lifespan. By identifying altered metabolites and metabolic networks at micrometer scale, we will generate high resolution profiles of brains from aged human APOE mice with and without AD pathology, as well as in clinically-characterized postmortem human brain tissue from young, old and AD individuals with various APOE genotypes. Finally, we will use ex vivo aged mouse microglia to determine the extent to which metabolic reprogramming of E4 microglia recovers aging and AD-related dysfunctional responses. If successful, these highly translational aims could provide new targets to normalize microglial metabolism and downstream inflammatory cascades, and thus potentially prevent or delay onset of AD in high-risk individuals.
|Effective start/end date||1/14/22 → 1/13/23|
- Cure Alzheimers Fund: $172,500.00
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