Re-wiring CSF1-R Signaling in Alzheimer’s Disease

Alzheimer’s disease (AD) is the leading cause of dementia, affecting over 6.9 million people in the US. Emerging evidence underscores the role of the brain’s immune system, particularly microglia, in AD-related neurodegeneration. Microglia transition from a protective "homeostatic" state to a "disease-associated" (DAM) state under chronic AD pathology, impairing phagocytosis, disrupting immune function, and accelerating neurodegeneration. This transformation is driven by signaling pathways and receptors like colony-stimulating factor-1 receptor (CSF1-R), which regulates processes such as phagocytosis, polarization, and proliferation. Studies suggest CSF1-R-mediated microglial depletion improves cognitive function in AD models. However, how Aβ disrupts CSF1-R signaling, impairing microglial function and driving disease progression, remains unclear. My hypothesis is that CSF1-R control of downstream signaling events and microglial phenotype are perturbed by exposure to AD pathogen Aβ. The goal of this proposal is three-fold: (Aim 1) determine how Aβ interacts with CSF1-R and its effect on specific CSF1-R phosphosite activity and its downstream signaling cascades in-vitro, (Aim 2) illuminate how dysregulated CSF1-R-mediated signaling impacts microglial phenotype (in vivo, in vitro ) and (Aim 3) identify AD-driven proteomic and transcriptomic signatures associated with CSF1-R activity and downstream signaling from human samples. This research proposal aims to provide a mechanistic insight into how AD pathology alters CSF1-R signaling and its downstream effectors. Identifying mechanisms through which disturbed CSF1-R signaling contributes to DAM phenotype and pathogenesis in AD could ultimately lead to a new paradigm for AD therapeutic development.