Investigating the role of brain-engrafted monocyte-derived macrophages in Alzheimer's disease

Washington University, Saint Louis MO

Investigators

Abstract

PROJECT SUMMARY Alzheimer’s disease (AD), the leading cause of dementia worldwide, affects millions of individuals and presents a major public health challenge. Microglia, the resident macrophages in the brain, adopt a range of activation states, displaying functional heterogeneity that spans from neuroprotective to neuroinflammatory roles in AD. Deciphering the heterogeneity of brain macrophage is essential for understanding the immune mechanisms driving AD pathogenesis. A key factor shaping macrophage heterogeneity is their ontogeny, as the developmental origin of macrophages plays a critical role in defining their identity and function. Microglia were thought to originate solely from yolk sac (YS) progenitors and maintain themselves through self-renewal without contributions from peripheral cells. However, recent studies suggest that monocyte-derived macrophages (MDMs) can infiltrate the brain under certain conditions, such as in mouse models of amyloidosis, adding to the heterogeneity of brain macrophages. However, the role of brain-engrafted MDMs in AD pathogenesis remains unclear. This research proposal aims to elucidate the contributions of brain-engrafted MDMs to AD pathology in both mouse models and human AD. In the F99 phase, I will investigate the effects of brain-engrafted MDMs on amyloid plaque deposition in the 5xFAD mouse model. Specifically, I will assess how promoting (Aim 1.1) or depleting (Aim 1.2) brain-engrafted MDMs affects amyloid accumulation and cognitive decline, providing insights into the functional role of MDMs in AD progression in mice. In the K00 phase, I will focus on studying human AD, utilizing somatic mosaicism as a method to trace brain-engrafted MDMs and investigate the role of AD- associated somatic mutations in human iPSC-derived microglia. A recent study revealed an enrichment of somatic mutations in AD patient microglia, suggesting that mutation-driven clonal expansion may contribute to AD pathology. However, it remains unclear whether MDMs infiltrating the human AD brain contribute to this mutational burden. I will analyze microglia and paired blood monocytes from AD patients and controls to determine whether peripherally-derived MDMs contribute to the increased somatic mutations observed in AD microglia. Additionally, I will introduce the top AD-associated somatic mutations into iPSC-derived microglia to assess their functional impacts on microglia. The successful completion of these studies will deepen our understanding of brain macrophage heterogeneity, particularly the distinct roles of MDMs versus YS-derived microglia in AD. This work holds the potential to uncover novel therapeutic targets aimed at slowing disease progression and improving outcomes for AD patients.