Rejuvenating Amyloid-Induced Dysfunction in the Oligodendrocyte–Microglial Niche via Youth-Associated Blood-Borne Factors

Dr. Castellano proposes to investigate how amyloid pathology disrupts the brain’s ability to repair myelin, the protective insulation surrounding nerve fibers that is essential for healthy neuronal communication. Rather than focusing solely on removing amyloid, the project examines how amyloid alters the interactions between oligodendrocytes (the cells that produce myelin), microglia, and the structural scaffolds surrounding cells, creating an environment that prevents normal myelin repair. The team hypothesizes that restoring this cellular niche using specific factors found in young blood can promote myelin repair and improve brain resilience despite ongoing amyloid pathology.

The project will combine single-cell sequencing, advanced imaging, and mouse models of amyloid pathology to define the mechanisms underlying these processes. In Aim 1, the investigators will determine how youth-associated blood-borne factors alter states and interactions among cell types and which cells are critical for maintenance of the niche. Aim 2 will test whether remodeling of the niche, either by reducing specific structural proteins or through delivery of a youth-associated plasma factor restores oligodendrocyte function and myelin repair in amyloid-bearing mice. Together, these studies aim to identify a previously unexplored therapeutic strategy that complements amyloid-targeting approaches by restoring the brain’s intrinsic capacity for repair to improve neuronal function.