Innate Immunity Fights Alzheimer's Disease

Alzheimer's disease (AD) is the most common age-related dementia. Pathognomonic accumulation of cerebral β-amyloid plaques likely results from imbalanced production and removal of amyloid-β (Aβ) peptides. In AD, innate immune cells lose their ability to restrict cerebral Aβ accumulation. At least in principle, mononuclear phagocytes can be enlisted to clear Aβ/β-amyloid from the brain. While the classical focus has been on dampening neuroinflammation in the context of AD, we hypothesize that rebalancing cerebral innate immunity by inhibiting actions of key anti-inflammatory cytokines returns the brain to a physiological state. Recent experiments demonstrating beneficial effects of blocking anti-inflammatory cytokine signaling in preclinical mouse models provide supportive evidence. This concept represents an important step toward innate immune-targeted therapy to combat AD.

TrendsRecent GWAS have identified a cluster of AD risk alleles belonging to core innate immune pathways that modulate phagocytosis.Functional polymorphism within the IL10 gene has been linked to increased risk for LOAD in certain populations, and IL-10 signaling is abnormally elevated in AD patient sera and brains.Inhibiting IL-10/STAT3 signaling dramatically mitigates AD-like pathology, while brain overexpression of IL-10 aggravates Aβ deposition in mouse models of cerebral amyloidosis.Elevated IL-10 signaling reduces Aβ clearance by mononuclear phagocytes and licenses ApoE–Aβ binding.IL-10/STAT3 pathway blockade enhances microglial Aβ phagocytic activity and decreases ApoE expression, thereby mitigating ApoE–Aβ binding that retards Aβ phagocytosis.Blocking anti-inflammatory mediators represents a promising future treatment approach for AD.