AD risk genes, MS4A4A and MS4A6A, alter microglial response to disease-relevant stimuli Amanda McQuade1, Jean-Paul Chadarevian1, Ian Smith1, Giovanni Coppola2 , Mathew Blurton-Jones1 1University of California, Irvine 2University of California, Los Angeles
Alzheimer's disease (AD) is the most common form of age-related dementia and is characterized by parenchymal deposits of beta amyloid, tau neurofibrillary tangles, and microgliosis, all of which precede the development of cognitive impairment. Recent genome wide association studies (GWAS) have uncovered a new cohort of AD risk genes, the majority of which are highly or even exclusively expressed by microglia, the immune cells of the brain. The function of many of these risk genes is currently unknown, and thus understanding the role of these genes in normal microglial function as well as AD pathogenesis could be highly informative. Of these new GWAS-identified risk genes, the Membrane-Spanning 4-Domains (MS4A) gene cluster is one of the most significantly associated with AD risk. In particular, two genes in this family, MS4A4A and MS4A6A, are specifically expressed in human microglia, but not in other parenchymal cells. Furthermore, eQTL studies have suggested that AD risk polymorphisms in the MS4A cluster correlate with measurable changes in MS4A4A and MS4A6A expression, making them a strong choice for understanding how changes in microglial MS4A expression might influence disease onset or progression. We therefore used siRNA-mediated gene silencing to examine the impact of MS4A4A and MS4A6A knockdown on human microglial gene expression and function. Our RNA sequencing results highlight disruptions in several disease relevant pathways including calcium signaling, mitochondrial dysfunction, and phagocytic pathways. In addition, ongoing functional validation of these pathways has corroborated many of these sequencing results and suggests that MS4A4A and MS4A6A play important roles in microglial bioenergetics, calcium signaling, and phagocytic activity. By working to understand how AD risk genes effect microglial function, we can begin to understand the important role of microglia in Alzheimer's disease.
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