Investigating the molecular basis of risk and resilience to Alzheimer's disease

National Institute Of Diabetes And Digestive And Kidney Diseases

Investigators

Linked publications, trials & patents

Abstract

This year our lab focused on establishing key workflows to address a number of key research areas. These include: (1) identifying and characterizing the structure and function of rare and protective APOE variants, (2) understanding the relationship between lipid metabolism and neuroinflammation (and it's perturbation by Alzheimer's risk factors), (3) understanding the role of genetic modifiers in reversing APOE-mediated perturbations to endocytic trafficking. To these ends, we have optimized a workflow to conduct deep mutational scanning and identified novel protective variants in APOE sequence. We have also established high throughput differentiation of human microglia from induced pluripotent stem cells and characterized perturbations to their lipid metabolism. We have characterized modulators of lipid metabolism and their effects on microglial activation. Our efforts have complemented the work of other investigators at the NIH and beyond including multiple at the Center for Alzheimers and Related Dementias (CARD); these include Andrew Singleton, Mark Cookson, and Michael Ward and the iPSC Neurodegenerative Disease Initiative team. We also have established key metabolomics characterization pipeline collaborations with Ruin Moaddel and Madhav Thambisetty at NIA.