Li- Huei Tsai, PhD
Director, Picower Institute for Learning and Memory

Massachusetts Institute of Technology

Lipid Dysregulation Is A Common Pathogenic Mechanism of Alzheimer's Disease Risk Genes

Alzheimer's disease (AD) is a debilitating brain disorder with staggering human and financial costs. While several genetic AD risk factors have been identified, we still lack a comprehensive understanding of how these variants disrupt cellular, molecular, and neural circuit processes in the brain, especially in the context of AD pathology. My lab uses multi-pronged computational and experimental approaches to address these knowledge-gaps. Recently, we reported the first single-nucleus transcriptomic atlas of the human prefrontal cortex, in which we identified widespread AD pathology-associated disruptions to all major brain cell types. Among these disruptions, we observed profound transcriptional changes related to myelin, the lipid-rich sheath insulating axons. To uncover potential genetic mediators of these AD-associated effects, we profiled single cell transcriptomes from human brains carrying the Apolipoprotein E4 variant (APOE4). While APOE4 is the strongest genetic risk factor for late onset AD, we do not yet fully understand how this risk variant contributes to AD pathogenesis. Our post-mortem transcriptomic data revealed that APOE4 was associated with widespread lipid perturbations, even in cells expressing low levels of the gene. Further experimental work revealed that these lipid perturbations induced states of demyelination and led to impaired cognitive performance. Subsequent single-cell transcriptomic profiling of post-mortem brains carrying ABCA7 loss-of-function variants, additional key AD risk variants, also indicated that these variants induced frequent lipid disruptions in the brain. Together, these data suggest that multiple key AD risk variants act by modifying lipid homeostasis in the brain. We propose that these lipid-centric perturbations increase AD risk by inducing vulnerable cellular states (e.g. demyelination) that can precipitate cognitive decline.  

Host Information: Bianca Corjuc ([email protected]) - Ramachandran Lab

The Columbia Neuroscience Seminar series is a collaborative effort of Columbia's Zuckerman Institute, the Department of Neuroscience, the Doctoral Program in Neurobiology and Behavior and the Columbia Translational Neuroscience Initiative, and with support from the Kavli Institute for Brain Science.