Abstract
The failure of brain microglia to clear excess amyloid β (Aβ) 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 Aβ by microglia. We first identified in the AD brain, in vivo and ex vivo, a subpopulation of microglia that express high Aβ phagocytic activity. Time-lapse microscopy showed that co-culturing newborn NPCs with microglia induced a significant increase in the fraction of microglia with high Aβ phagocytic activity. Freshly isolated NPCs from adult wild type, but not AD, mouse brain, induced an increase in the fraction of microglia with high Aβ phagocytic activity. Finally, we showed that NPCs also possess the ability to promote Aβ degradation within the microglia with high Aβ phagocytic activity. Thus, resident brain NPCs support microglial function to clear Aβ, but NPCs derived from the AD environment fail to do so. We suggest that the failure of AD brain NPCs to support Aβ clearance from the brain by microglia may accelerate disease pathology.
Highlights
Both the familial and late-onset forms of Alzheimer’s disease (AD) manifest with early deposition of amyloid β (Aβ) in the brain, occurring decades before clinical presentation of dementia symptoms [1,2]
We show that Neural precursor cells (NPCs) derived from adult mouse AD brains fail to support microglial phagocytic activity
This phenotype was acquired by the effect of the AD brain environment, as 7-month-old microglia from 5xFAD mice exhibited a significantly increased phagocytic activity compared to the microglia from 2-month-old 5xFAD mice (Figure 1C,D, p = 0.0334) [19,28,29]
Summary
Both the familial and late-onset forms of Alzheimer’s disease (AD) manifest with early deposition of amyloid β (Aβ) in the brain, occurring decades before clinical presentation of dementia symptoms [1,2]. It is thought that early in the course of disease they function to remove excess Aβ from accumulating in the brain, but eventually fail in this task [6]. Microglia are activated to a neurotoxic state by misfolded Aβ and phosphorylated tau [4,7]. This state of massive activation of microglia displays paradoxical functional failure, contributing to the progression of AD by failing to clear Aβ plaques, and damaging neurons via nitric oxide, reactive oxygen species, and cytokine production [8]
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