Inflammatory mechanisms in neurodegeneration

Abstract

This review discusses the profound connection between microglia, neuroinflammation, and Alzheimer's disease (AD). Theories have been postulated, tested, and modified over several decades. The findings have further bolstered the belief that microglia-mediated inflammation is both a product and contributor to AD pathology and progression. Distinct microglia phenotypes and their function, microglial recognition and response to protein aggregates in AD, and the overall role of microglia in AD are areas that have received considerable research attention and yielded significant results. The following article provides a historical perspective of microglia, a detailed discussion of multiple microglia phenotypes including dark microglia, and a review of a number of areas where microglia intersect with AD and other pathological neurological processes. The overall breadth of important discoveries achieved in these areas significantly strengthens the hypothesis that neuroinflammation plays a key role in AD. Future determination of the exact mechanisms by which microglia respond to, and attempt to mitigate, protein aggregation in AD may lead to new therapeutic strategies.

Keywords: Alzheimer's disease; amyloid-beta; microglia; neuroinflammation.

Figure 1.

Mechanisms of Aβ-mediated neuroinflammation. Interactions between microglia and various conformational forms of Aβ involve stimulation of cell-surface receptors and internalization by non-receptor mechanisms. Either interaction can provoke pro-inflammatory cytokine release through multiple intracellular pathways. Two key processes involve NFκB-mediated transcription/translation of cytokines such as TNFα and pro-IL-1β followed by NLRP3 inflammasome-mediated cleavage of pro-IL-1β to mature IL-1β. Internalized Aβ can trigger inflammasome activity and this may occur via endosomal or lysosomal factors.

Figure 2.

Bi-directional relationship between microglia and plaque deposition. Significant evidence indicates that Aβ aggregation and accumulation in plaque deposits leads to changes in microglia phenotype and microglia-mediated neuroinflammation. However, many studies also demonstrate that the microglial functional state can, in turn, modulate Aβ aggregation, plaque deposition, and pathology. Mechanisms by which microglia may negatively modulate Aβ aggregation or spread may include phagocytosis or the formation of a tight barrier around plaques, while positive modulation may involve secretion of cytokines or seeding of Aβ by microglial cellular factors.