UC San Diego

Microglia are known as the guardians of the brain, acting as either an angel or an assassin. These brain resident macrophages serve as the brains very own immune system, phagocytosing debris and pruning neuronal synapses. A major focus in studying neurodegenerative diseases has been placed on neuronal compartments, often deemphasizing immunological mechanisms. Much evidence points towards microglia playing a role in these diseases, for example the number of GWAS (genome wide association studies) hits in Alzheimer’s disease. One of these hits is the apolipoprotein E (APOE), with the ε4 allele correlated with the highest risk and the ε2 allele to reduced risk, and ε3 allele being neutral. Using human cells to model human disease is crucial, as studies have shown numerous microglial differences between species. Here, I utilize a protocol to convert patient derived induced pluripotent stem cells (iPSCs) into induced microglia (iMGs) from 22 individuals to study how the APOE4 haplotype impacts microglial function. By studying microglia in vitro without perturbations, we can begin uncovering the cell autonomous roles APOE4 plays in microglia. By performing single cell RNA sequencing (scRNAseq), we uncover how APOE4 shifts the transcriptomic state of microglia away from disease associated microglia (DAM) and to include a senescent-like phenotype. This is reflected in the cellular bioenergetics and the lipid content of APOE4 microglia. We find that lysosomes in APOE4 microglia have an accumulation of cholesterol esters and using a liver x receptor (LXR) agonist, we are able to rescue these phenotypes, by reducing cholesterol esters and inducing autophagy. This study highlights the importance of stratifying patient populations in Alzheimer’s, as the mechanisms at play are different for APOE4 carrier. Finally, we highlight the importance of iPSC-based models in studying Alzheimer’s in a review. We discuss the potential of using human brain organoids to study disease and specifically how incorporating microglia into these models could help further uncover how microglia impact other cell types.