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Microglia in Alzheimer's Disease: Risk Factors and Inflammation

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Microglia in Alzheimer's Disease: Risk Factors and Inflammation

Atsuko Katsumoto et al. Front Neurol.

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.

Keywords: NLRP3; TBI; TREM2; glutamate; inflammasomes; microglia; neuroinflammation.

Figures

Figure 1
Figure 1
Implication of microglia in the development of Alzheimer's disease. (A) Several conditions are associated with an increased risk of developing AD. For example, variants in TREM2 ameliorate amyloid pathology in the early disease stage, but exacerbate pathology as the disease progresses. The TREM2-APOE pathway is responsible for switching from a homeostatic to a neurodegenerative microglial phenotype after phagocytosis of apoptotic neurons. Environmental factors also affect the microglial reaction to aggregated Aβ or phosphorylated tau. Head trauma also leads to a local increase in the levels of inflammatory mediators, which may stimulate Aβ generation and restrict phagocytic clearance. Likewise, microbiota influenced by diabetes or diet may regulate microglial phenotypes. (B) Aggregated Aβ or phosphorylated tau impairs synaptic functions, triggering the release of neurotoxic mediators from microglia. ATP, ADP, and adenosine activate NLRP3 inflammasomes, followed by the release of IL-1β. Similarly, glutamate released from gap junction hemichannels lead to massive neuronal damage. APP, amyloid precursor protein; PS, presenilin; ApoEε4, apolipoprotein Eε4; TREM2, triggering receptor expressed on myeloid cells 2; P2X(Y)R, purinergic receptor; A2ARs, adenosine A2A receptors; AR, adenosine receptor; DAMPs, damage-associated molecular patterns; NLRP3, NACHT, LRR, and PYD domains-containing protein 3; ASC, apoptosis-associated speck-like protein containing a caspase-recruitment domain.

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References

    1. He Z, Guo JL, McBride JD, Narasimhan S, Kim H, Changolkar L, et al. . Amyloid-β plaques enhance Alzheimer's brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat Med. (2018) 24:29–38. 10.1038/nm.4443 - DOI - PMC - PubMed
    1. Karch CM, Goate AM. Alzheimer's disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry (2015) 77:43–51. 10.1016/j.biopsych.2014.05.006 - DOI - PMC - PubMed
    1. Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, et al. . TREM2 variants in Alzheimer's disease. N Engl J Med. (2013) 368:117–27. 10.1056/NEJMoa1211851 - DOI - PMC - PubMed
    1. Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, et al. . Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med. (2013) 368:107–16. 10.1056/NEJMoa1211103 - DOI - PMC - PubMed
    1. Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, et al. . Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet. (2011) 43:429–35. 10.1038/ng.803 - DOI - PMC - PubMed

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