Failure of Alzheimer's Mice Brain Resident Neural Precursor Cells in Supporting Microglia-Mediated Amyloid β Clearance

The failure of brain microglia to clear excess amyloid beta (A beta) is considered a leading cause of the progression of Alzheimer's disease pathology. Resident brain neural precursor cells (NPCs) possess immune-modulatory and neuro-protective properties, which are thought to maintain brain homeostasis. We have recently showed that resident mouse brain NPCs exhibit an acquired decline in their trophic properties in the Alzheimer's disease brain environment. Therefore, we hypothesized that functional NPCs may support microglial phagocytic activity, and that NPCs derived from the adult AD mouse brain may fail to support the clearance of A beta by microglia. We first identified in the AD brain, in vivo and ex vivo, a subpopulation of microglia that express high A beta phagocytic activity. Time-lapse microscopy showed that co-culturing newborn NPCs with microglia induced a significant increase in the fraction of microglia with high A beta phagocytic activity. Freshly isolated NPCs from adult wild type, but not AD, mouse brain, induced an increase in the fraction of microglia with high A beta phagocytic activity. Finally, we showed that NPCs also possess the ability to promote A beta degradation within the microglia with high A beta phagocytic activity. Thus, resident brain NPCs support microglial function to clear A beta, but NPCs derived from the AD environment fail to do so. We suggest that the failure of AD brain NPCs to support A beta clearance from the brain by microglia may accelerate disease pathology.

Automated summary

Brain neural precursor cells (NPCs) support microglial function to clear excess amyloid beta (Aβ), but NPC from the Alzheimer's disease (AD) environment fail to do so, potentially accelerating disease pathology.