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

Abstract

This year our lab focused on advancing fundamental understanding of novel cellular mechanisms driving Alzheimer’s disease and identifying metabolic interventions with therapeutic potential. Alzheimer’s disease, like many neurodegenerative disorders, is a chronic disease marked by progressive cellular dysfunction. Our work has centered on uncovering how disturbances in lipid metabolism contribute to neuroinflammation and disease progression, and on finding strategies to reverse these changes. Our major research priorities included: 1) Defining the relationship between lipid metabolism and neuroinflammation, and its perturbation by Alzheimer’s risk factors. 2) Understanding the role of genetic modifiers in reversing APOE-mediated disruptions to cellular trafficking. 3) Identifying mechanisms and interventions that protect against APOE4-associated risk. We established high-throughput differentiation of human microglia from induced pluripotent stem cells (iPSCs) and characterized how APOE4 perturbs their lipid metabolism. We also identified and characterized modulators of lipid metabolism that can tune microglial activation states—pointing toward novel metabolic intervention strategies for chronic neurodegenerative disease. A major highlight was our publication (PMID: 40644302), which demonstrated that triglyceride biosynthesis is necessary for proper microglial response to inflammation but is hijacked by the APOE4 genotype to induce chronic inflammation. Inhibition of triglyceride biosynthesis can rescue APOE4 associated chronic inflammation as well as microglial surveillance defects. This work revealed that targeted modulation of triglyceride metabolism can recalibrate microglial immune activity, providing a potential metabolic intervention point for Alzheimer’s and related chronic diseases. We also isolated and purified lipid droplets from human iPSC-derived astrocytes to dissect how APOE variants shape lipid droplet composition. This led to a new paper on the human astrocytic lipid droplet proteome, revealing previously unrecognized protective mechanisms that may counteract disease-associated cellular stress. These efforts were amplified through collaborations with NIH colleagues, including Drs. Mark Cookson, Mioara Larion, Adrian Lita, Andy Qi as well as external partners such as Dr. Rebeck’s lab at Georgetown (on lipid effects on microglial motility) and Dr. van der Kant and Martin Giera in the Netherlands (on metabolomics pipelines). Together, our work positions lipid metabolism and cellular bioenergetics as central players in the pathogenesis and potential treatment of Alzheimer’s disease, and underscores the value of metabolic interventions in combating chronic neurodegenerative disorders.