Microglia in Alzheimer's Disease: A Favorable Cellular Target to Ameliorate Alzheimer's Pathogenesis

Abstract

Microglial cells serve as molecular sensors of the brain that play a role in physiological and pathological conditions. Under normal physiology, microglia are primarily responsible for regulating central nervous system homeostasis through the phagocytic clearance of redundant protein aggregates, apoptotic cells, damaged neurons, and synapses. Furthermore, microglial cells can promote and mitigate amyloid β phagocytosis and tau phosphorylation. Dysregulation of the microglial programming alters cellular morphology, molecular signaling, and secretory inflammatory molecules that contribute to various neurodegenerative disorders especially Alzheimer's disease (AD). Furthermore, microglia are considered primary sources of inflammatory molecules and can induce or regulate a broad spectrum of cellular responses. Interestingly, in AD, microglia play a double-edged role in disease progression; for instance, the detrimental microglial effects increase in AD while microglial beneficiary mechanisms are jeopardized. Depending on the disease stages, microglial cells are expressed differently, which may open new avenues for AD therapy. However, the disease-related role of microglial cells and their receptors in the AD brain remain unclear. Therefore, this review represents the role of microglial cells and their involvement in AD pathogenesis.

Figure 1

Role of Aβ in the activation of microglia to initiate Alzheimer's pathology. Aβ: amyloid beta; APP: amyloid precursor protein; IL-1: interleukin-1; IL-6: interleukin-6; TNF-α: tumor necrosis factor-α; MCP-1: monocyte chemotactic-1; MIP-1: macrophage inflammatory protein-1; HO: hydroxyl radical; H₂O₂: hydrogen peroxide; O₂: oxygen radical.

Figure 2

The linkage of microglia receptors in the pathogenesis of Alzheimer's disease. CR3 is responsible for the Aβ-induced microglial activation and involved in Aβ-mediated microglia free radical generation as well as uptake and clearance of Aβ. TLR2 is implicated in the generation of the inflammatory response. On the other hand, TLR4 (i.e., stimulated with LPS) is associated with the clearance of Aβ. Microglia cells showed an increase in Aβ uptake. The binding of Aβ to SRs internalizes Aβ and could activate inflammation responses and generate reactive species. Microglia RAGE-Aβ interaction triggers the genesis of proinflammatory molecules that causes neuronal destruction. PM: plasma membrane; Aβ: amyloid beta; CR: complement receptor; LPS: lipopolysaccharide; TLR: Toll-like receptor; SR: scavenger receptor; RAGE: receptor for advanced glycation end products; ROS: reactive oxygen species.

Figure 3

Possible mechanisms of action of activated microglia in different early and later stages of Alzheimer's disease. In the early stages of AD, activated microglia may increase Aβ clearance through TREM2 and scavenger receptors. On the other hand, in the late stage of the disease, continuous microglial activation induced by Aβ through various receptors triggers a vicious cycle of microglial activation, neuroinflammation, and Aβ buildup that leads to AD. AD: Alzheimer's disease; TLR: Toll-like receptor; RAGE: receptor for advanced glycation end products; IL-1β: interleukin-1β; TNF-α: tumor necrosis factor-α; ROS: reactive oxygen species; SR: scavenger receptor; TREM2: triggering receptor expressed on myeloid cell 2