Innate Immunity Fights Alzheimer's Disease

Abstract

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.

Keywords: amyloid; apolipoprotein E; immunotherapy; interleukin-10; microglia; phagocytosis.

Figure 1. Methodology for quantitative 3D in silico modeling (q3DISM) of Aβ phagocytosis

This multi-stage q3DISM technique is depicted. This cutting-edge technology allows for true 3D quantitation of Aβ phagocytosis in vivo by mononuclear phagocytes.

Figure 2. Il10 dependent neuroinflammatory gene profiles in mouse models of cerebral amyloidosis

The diagram shows the broad categories of major gene groups affected by experimental targeting of Il10 (overexpression or genetic ablation) according to transcriptomics published in [–33].

Figure 3. Proposed model for the impact of IL-10 on Aβ clearance by mononuclear phagocytes

The top panel depicts effects of supra-physiologic IL-10; present in AD brains and in mouse models of cerebral amyloidosis. IL-10/STAT3 pathway activation reduces monocyte Aβ phagocytosis. Concomitantly, ApoE expression is increased and clusters in Aβ deposits, retarding Aβ clearance. The lower panel illustrates effects of Il10 ablation in mouse models of cerebral amyloidosis. Microglial phagocytic capacity is enhanced and ApoE expression, reduced, enabling Aβ clearance by mononuclear phagocytes.