Human iPSC‐Derived Mononuclear Phagocytes Improve Cognition and Neural Health across Multiple Mouse Models of Aging and Alzheimer's Disease

Abstract Young blood or plasma improves cognitive function in aged animals but has limited availability. The current study generates a subtype of young blood cells from easily expandable induced pluripotent stem cells and evaluates their effects on age‐ and Alzheimer's disease (AD)‐associated cognitive and neural decline. In aging mice, intravenous delivery of induced mononuclear phagocytes (iMPs) improves performance in hippocampus‐dependent cognitive tasks, increases neural health, and reduces neuroinflammation. Hippocampal single nucleus RNA‐sequencing shows that iMPs improve the health of a subpopulation of mossy cells that are critically involved in the type of cognitive task in which iMPs improve performance, and shows that iMPs decrease the transcriptional age of several hippocampal cell types. Plasma proteomic analyses reveal that iMPs can also reverse age‐associated increases in serum amyloid levels. This is verified in vitro, where iMP‐conditioned media is shown to protect human microglia against cell death induced by serum amyloids. Finally, iMPs improve cognition in both young and aging 5×FAD mice, highlighting their potential as a prevention as well as an intervention strategy. Together, these findings suggest that iMPs provide a novel therapeutic strategy to target both age‐ and AD‐related cognitive decline.