PROJECT SUMMARY Peripheral monocytes are of therapeutic interest in Alzheimer’s Disease because they are capable of clearing fibrillar amyloid β and can be targeted more readily than the brain’s resident microglia, which become defective in their ability to clear amyloid β plaques and contribute to neuroinflammation in Alzheimer’s patients. Indeed, peripheral monocytes have been shown to promote amyloid β plaque clearance, reduce neuroinflammation, preserve synapses and improve cognitive function in Alzheimer’s Disease mouse models. However, monocytes are heterogeneous, and little is known about the amyloid β responsiveness and neuroprotective properties of monocyte subsets. We recently demonstrated that functionally distinct classical monocyte subsets arise independently from granulocyte-monocyte progenitors (GMPs) and monocyte-dendritic cell progenitors (MDPs) in mouse bone marrow. Our analysis of GMP- and MDP-derived classical monocyte gene expression also revealed that MDP-derived monocytes express higher levels of several genes that have been implicated in amyloid β binding and clearance than their GMP-derived counterparts. In particular, MDP-derived monocytes express 50-fold more angiotensin converting enzyme (ACE). Our collaborators, Drs. Maya Koronyo-Hamaoui and Kenneth Bernstein, have previously shown that monocytes overexpressing ACE clear amyloid β more effectively than wild type monocytes and protect against neurodegeneration following peripheral administration in Alzheimer’s Disease mice. The central goal of this study is to determine how monocyte origins impact the ability of peripheral monocytes and macrophages to clear and respond to amyloid β. We hypothesize that MDP-derived monocytes and macrophages bind and clear amyloid β more effectively and are less inflammatory than their GMP-derived counterparts. To test this hypothesis, we will derive monocytes and macrophages from GMPs and MDPs and compare their ability to detect and internalize fibrillar amyloid β (Aim 1), as well their production of pro- and anti-inflammatory cytokines in response to stimulation with fibrillar amyloid β (Aim 2). This project will open a new avenue of investigation for the research team, building on Dr. Goodridge’s research on the origins and functional diversity of monocyte subsets and expanding the current focus beyond pathogen defense by facilitating a new collaboration to define the therapeutic implications of monocyte heterogeneity in the context of Alzheimer’s Disease.