Microglial Phagocytosis: A Disease-Associated Process Emerging from Alzheimer's Disease Genetics. Issue 12 (December 2020) - Podleśny-Drabiniok, Anna
Abstract : Alzheimer's disease (AD) is a debilitating, chronic neurodegenerative disease. Genetic studies involving genome-wide association studies (GWAS) and meta-analysis have discovered numerous genomic loci associated with AD; however, the causal genes and variants remain unidentified in most loci. Integration of GWAS signals with epigenomic annotations has demonstrated that AD risk variants are enriched in myeloid-specific enhancers, implicating myeloid cells in AD etiology. AD risk variants in these regulatory elements modify disease susceptibility by regulating the expression of genes that play crucial roles in microglial phagocytosis. Several of these AD risk genes are specifically expressed in myeloid cells, whereas others are ubiquitously expressed but are regulated by AD risk variants within myeloid enhancers in a cell type-specific manner. We discuss the impact of established AD risk variants on microglial phagocytosis and debris processing via the endolysosomal system. Highlights: Genetic variants associated with Alzheimer's disease (AD) are enriched in myeloid-specific enhancers, including microglial enhancers, implicating this cell type in the etiology of AD. AD risk variants in these enhancers modulate disease susceptibility by regulating enhancer activity and in turn the expression of genes involved in microglial phagocytosis and the endolysosomal pathway. Common risk variants are enriched for proteins expressed in early endosomes. Pathway analysis of AD genetics combined with myeloid genomics strongly implicates dysregulation of phagocytosis of tissue debris in the etiology of AD.