Investigating Lysosomal Mechanisms of Risk and Resilience in Alzheimer’s Disease

APOE4 is the strongest genetic risk factor for Alzheimer’s disease (AD). Personalized genotyping products increasingly are enabling individuals to identify whether they are carriers of APOE4 or other genetic risk factors for cognitive impairments. However, we have a limited understanding of how APOE4 increases the risk for cognitive impairments. As a result, there currently are no lifestyle or therapeutic interventions to minimize these known genetic risks. Using patient-derived stem cells, we engineered a human brain tissue in vitro that contains neurons, vasculature, and immune and glial cells. This multicellular integrated brain (miBrain) recapitulates key anatomical and physiological aspects of human brain tissue in a dish. Combining this technology with CRISPR genome editing, we generate genetically identical sets of human brain tissue that differ only by APOE genotype. This enables us to replay the biological events of AD in a controlled laboratory setting to determine precisely how APOE4 influences the development of tau pathology. We have optimized methods for inducing tau. Our studies found that APOE4 astrocytes are necessary and sufficient to increase pathological phenotypes of tau in the miBrain. Focusing on astrocytes, we found that in APOE4 astrocytes, lysosomal function is impaired and correlates with increased cholesterol accumulation. Here, we will further investigate the mechanistic connection between APOE genotype, cholesterol and lysosomal function in risk for and resilience to AD. We also will perform small molecule screens to identify novel therapeutic opportunities.