Identification of modifiers of APOEe4 toxicity
Women are more at risk for developing AD, and the impact of APOEε4 isoforms is greater in women. Also, immune response is different between men and women, making the effect of APOE in microglia vulnerable to sex differences. To understand how sex and genetic backgrounds participate in APOEε4 toxicity in LOAD, we will examine induced pluripotent stem cell lines collected from 60 donors carrying an APOEε4 allele. We will assess the role of APOE expression itself and the impact of sex in microglial response answering the following questions: 1) What is the contribution of APOE protein itself on microglia function, 2) How does APOEε4 interact with sex to alter microglia states and functions? and 3) How does the pathogenic brain environment impact microglia expression?
NEUROIMMUNE CONSORTIUM: IMPACT OF AD POLYGENIC RISK SCORE ON MICROGLIAL RESPONSE TO PERIPHERAL INFLAMMATION
Microglia are the brain’s immune cells and express multiple Alzheimer’s disease (AD) risk genes. Understanding the impact of these risk genes on microglia is essential to identify how disease is initiated and progresses. Recently, it has been shown that peripheral inflammation is a major component of AD pathogenesis, but we don’t know how microglia respond to this specific inflammation. In this study, we will use stem cell models to understand how AD genetic risk alters the response of human microglia to peripheral inflammation. This project will identify new pathways by which microglia become dysfunctional in disease, and highlight how they impact other brain cells and disease progression.
MDA Development Grant 2022
Although most therapeutic avenues for Amyotrophic lateral sclerosis (ALS) have focused on neurons, recent studies suggest that microglia, the immune cells of the brain, are key players in pathogenesis, pointing toward alternative approaches to therapeutic development. Many genetic risk factors for ALS are expressed in microglia and recently, a distinct subpopulation, or “state”, has been identified in ALS patients. Interestingly, microglia have also been involved in other neurodegenerative diseases like Alzheimer’s disease. In this study, we used human cell culture models and single-cell-resolution analyses to identify how ALS genetics affect microglia states and functions and understand how microglia affect motor neuron health. This project will identify pathways of neurodegeneration specific to ALS and open the door for new therapeutic avenues.