Abstract
Microglia are resident immune cells in the central nervous system (CNS) that originate from myeloid progenitor cells in the embryonic yolk sac and are maintained independently of circulating monocytes throughout life. In the healthy state, microglia are highly dynamic and control the environment by rapidly extending and retracting their processes. When the CNS is inflamed, microglia can give rise to macrophages, but the regulatory mechanisms underlying this process have not been fully elucidated. Recent genetic studies have suggested that microglial function is compromised in Alzheimer's disease (AD), and that environmental factors such as diet and brain injury also affect microglial activation. In addition, studies of triggering receptor expressed on myeloid cells 2-deficiency in AD mice revealed heterogeneous microglial reactions at different disease stages, complicating the therapeutic strategy for AD. In this paper, we describe the relationship between genetic and environmental risk factors and the roles of microglia in AD pathogenesis, based on studies performed in human patients and animal models. We also discuss the mechanisms of inflammasomes and neurotransmitters in microglia, which accelerate the development of amyloid-β and tau pathology.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disease
In this regard, coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) gene confer the highest AD risk, indicating that microglial neuroinflammation plays a critical role in AD progression [3, 4]
In accordance with these findings, a single-nucleotide polymorphism in the gene encoding the microglial surface receptor CD33 reduces Aβ phagocytosis by peripheral macrophages isolated from carriers of heterozygous and homozygous mutations [5,6,7] supporting the hypothesis that microglial function is compromised
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disease. AD brains are characterized by the combined presence of two structures: extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles. Recent genetic studies have identified variants in immune-related genes that increase the risk of developing AD [2], implicating the neuroinflammatory response in AD pathogenesis In this regard, coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) gene confer the highest AD risk, indicating that microglial neuroinflammation plays a critical role in AD progression [3, 4]. Microglia in Alzheimer’s Disease phenotypic heterogeneity of microglia: the early response state is characterized by marked proliferation, whereas the late response state is associated with mounting immune responses [9] In the latter state, two functionally distinct reactive microglial phenotypes, typified by modules of co-regulated type 1 and type 2 interferon response genes, have been identified [9]. We review how genetics and environmental factors influence microglial functions, and illustrate the therapeutic targets in AD, with special emphasis on microglial inflammasomes and neurotransmitters
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