Sara Bitarafan

BioE PhD Defense Presentation

Apr 2, 2026 12:00 PM Eastern Time

1128 IBB/ Suddath room

https://gatech.zoom.us/j/99208014089

Meeting ID: 992 0801 4089

Dr. Levi B. Wood, Advisor-Woodruff School of Mechanical Engineering, Georgia Institute of Technology

Dr. Young Jang, Emory Musculoskeletal Institute, Department of Orthopedics, Wallace H. Coulter Department of Biomedical Engineering Emory School of Medicine & Georgia Institute of Technology

Dr. Melissa Kemp, Wallace H. Coulter Department of Biomedical Engineering, Emory School of Medicine & Georgia Institute of Technology

Dr. Srikant Rangaraju, Department of Neurology, Yale University

Dr. Annabelle Singer, Wallace H. Coulter Department of Biomedical Engineering, Emory School of Medicine & Georgia Institute of Technology

Rewiring CSF1R signaling in Alzheimer’s disease

Alzheimer's disease (AD) is the leading cause of dementia, affecting approximately 7 million people in the United States, yet no effective cure exists. The repeated failure of therapies targeting amyloid beta (Aβ) underscores the complexity of the disease and has shifted attention toward neuroinflammatory mechanisms, particularly the role of microglia. Colony stimulating factor 1 receptor (CSF1R) is the predominant regulator of microglial survival and function in the brain and has been widely used as a tool to deplete microglia. Despite its established role in microglial biology, the mechanisms by which AD pathology alters CSF1R signaling and its downstream consequences for microglial behavior remain poorly understood. Here, I investigated whether the AD microenvironment reshapes CSF1R-mediated signaling in a context-dependent manner and whether this transformation can be therapeutically exploited. Proteomic analysis of postmortem human AD brain tissue revealed that CSF1R co-expressed protein networks are completely distinct from those of age-matched controls, with disease-associated networks enriched for neurodegeneration and inflammatory pathways. Across multiple in vitro systems, Aβ pre-exposure consistently reprogrammed CSF1R signaling, driving sustained MAPK-ERK activation, suppression of Akt-mTOR, and site-specific transformation of CSF1R tyrosine phosphorylation. Notably, CSF1-induced ERK hyperactivation was identified as a primary driver of impaired microglial phagocytosis in the Aβ-primed state, establishing a direct mechanistic link between disease-driven CSF1R rewiring and microglial dysfunction. In vivo, CSF1R inhibition with BLZ945 in 5xFAD mice promoted microglial activation, normalized inflammatory proteomic signatures, and fully restored post-synaptic density after just 6 daily doses, effects entirely absent in wild-type animals. These findings demonstrate that CSF1R is not a static on-off switch for microglial activation, but a context-dependent signaling hub whose output is fundamentally shaped by the disease microenvironment. A deeper understanding of how AD pathology transforms CSF1R signaling and downstream microglial function will be essential for developing more targeted and effective therapeutic approaches for AD.