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Genetic Risk Factors for Alzheimer Disease: Emerging Roles of Microglia in Disease Pathomechanisms

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Reviews on Biomarker Studies in Psychiatric and Neurodegenerative Disorders

Part of the book series: Advances in Experimental Medicine and Biology ((PMISB,volume 1118))

Abstract

The accumulation of aggregated amyloid β (Aβ) peptides in the brain is deeply involved in Alzheimer disease (AD) pathogenesis. Mutations in APP and presenilins play major roles in Aβ pathology in rare autosomal-dominant forms of AD, whereas pathomechanisms of sporadic AD, accounting for the majority of cases, remain unknown. In this chapter, we review current knowledge on genetic risk factors of AD, clarified by recent advances in genome analysis technology. Interestingly, TREM2 and many genes associated with disease risk are predominantly expressed in microglia, suggesting that these risk factors are involved in pathogenicity through common mechanisms involving microglia. Therefore, we focus on factors closely associated with microglia and discuss their possible roles in pathomechanisms of AD. Furthermore, we review current views on the pathological roles of microglia and emphasize the importance of microglial changes in response to Aβ deposition and mechanisms underlying the phenotypic changes. Importantly, functional outcomes of microglial activation can be both protective and deleterious to neurons. We further describe the involvement of microglia in tau pathology and the activation of other glial cells. Through these topics, we shed light on microglia as a promising target for drug development for AD and other neurological disorders.

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Acknowledgment

This work was supported in part by Grant-in-Aid for Scientific Research (A) [15H02492 to T.T.] and Grant-in-Aid for Young Scientists (B) [17K15446 to S.T.] from the Japan Society for the Promotion of Science (JSPS), by the Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) from the Japan Agency for Medical Research and Development (AMED) [JP18dm0207014h to T.T.], by the Sunbor Grant from the Suntory Foundation for Life Sciences [to S.T.], by the Uehara Memorial Foundation [to T.T.], and by the Mitsubishi Foundation [to T.T.].

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  1. Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan

    Sho Takatori, Wenbo Wang, Akihiro Iguchi & Taisuke Tomita

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  1. Sho Takatori
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  2. Wenbo Wang
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Correspondence to Taisuke Tomita .

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  1. Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil

    Paul C. Guest

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Takatori, S., Wang, W., Iguchi, A., Tomita, T. (2019). Genetic Risk Factors for Alzheimer Disease: Emerging Roles of Microglia in Disease Pathomechanisms. In: Guest, P. (eds) Reviews on Biomarker Studies in Psychiatric and Neurodegenerative Disorders. Advances in Experimental Medicine and Biology(), vol 1118. Springer, Cham. https://doi.org/10.1007/978-3-030-05542-4_5

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