Define causal transcription factor networks that drive protective or pathogenic microglia phenotypes in Alzheimer’s Disease
There is compelling evidence that microglia play both protective and pathogenic roles in the development of Alzheimer’s disease (AD) and other neurodegenerative diseases. Despite substantial efforts, we do not yet understand the basic mechanisms that drive these divergent phenotypes, nor do we understand how these mechanisms combine in microglia to achieve specific cell states. Even in the case of proteins that are genetically linked to protective or pathogenic roles, such as TREM2 or APOE respectively, major knowledge gaps remain in connecting risk alleles to the downstream genes that determine disease outcomes. Thus, a key gap in our understanding of the role of microglia in the pathogenesis of AD is how different cell states are initiated and regulated by transcription factors. Additionally, several transcription factors implicated in regulating microglial states are also in AD risk loci, thus directly implicating regulation of microglial state in response to Aβ and the disease environment in AD risk. We aim to use human-focused epigenetic approaches and tools developed in the Epigenetics Working Group to identify regulatory pathways that drive microglial cell states and understand how those pathways are altered in disease. Filling these gaps will inform existing and novel strategies to target microglia for therapeutic purposes in AD.
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.