Microglia in the Neuroinflammatory Pathogenesis of Alzheimer's Disease and Related Therapeutic Targets

Abstract

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease worldwide, characterized by progressive neuron degeneration or loss due to excessive accumulation of β-amyloid (Aβ) peptides, formation of neurofibrillary tangles (NFTs), and hyperphosphorylated tau. The treatment of AD has been only partially successful as the majority of the pharmacotherapies on the market may alleviate some of the symptoms. In the occurrence of AD, increasing attention has been paid to neurodegeneration, while the resident glial cells, like microglia are also observed. Microglia, a kind of crucial glial cells associated with the innate immune response, functions as double-edge sword role in CNS. They exert a beneficial or detrimental influence on the adjacent neurons through secretion of both pro-inflammatory cytokines as well as neurotrophic factors. In addition, their endocytosis of debris and toxic protein like Aβ and tau ensures homeostasis of the neuronal microenvironment. In this review, we will systematically summarize recent research regarding the roles of microglia in AD pathology and latest microglia-associated therapeutic targets mainly including pro-inflammatory genes, anti-inflammatory genes and phagocytosis at length, some of which are contradictory and controversial and warrant to further be investigated.

Keywords: alzheimer’s disease; anti-neuroinflammation; microglial cells; molecular therapy; neuroinflammation.

Figure 1

The role of microglia in AD progression. The clearance of Aβ mediated by microglia contributes to the homeostasis maintenance of CNS. But, with the AD progression, excessive activation of microglia would release excessive pro-inflammatory factors to compromise neurons and their synapses.

Figure 2

NLRP3 inflammasome and IDE in microglia of AD. The NLRP3 inflammasome accelerates microglial inflammation and can be inhibited by various substances. The secretion of IDE helps degrade Aβ and is regulated by diverse drugs.

Figure 3

NF-κB pathway in microglia of AD. NF-κB signal pathway plays a central role in microglia-mediated neuroinflammation. This figure introduces multiple drugs mentioned in this review above, and their effects on microglia at length via NF-κB signal pathway.

Figure 4

Microglial phagocytosis and autophagy in AD. Microglia eliminate Aβ load through phagocytosis and autophagy. This figure displays the regulatory mechanism of this process.