Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Adv Exp Med Biol. 2019;1118:83-116. doi: 10.1007/978-3-030-05542-4_5.
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.
淀粉样β (Aβ) 肽的聚集在阿尔茨海默病 (AD) 的发病机制中起着重要作用。APP 和早老素的突变在 AD 的罕见常染色体显性遗传形式中起主要作用，而占大多数病例的散发性 AD 的发病机制仍然未知。在这一章中，我们回顾了 AD 的遗传风险因素的最新知识，这些知识是通过基因组分析技术的最新进展澄清的。有趣的是，TREM2 和许多与疾病风险相关的基因主要在小胶质细胞中表达，这表明这些风险因素通过涉及小胶质细胞的共同机制参与了致病性。因此，我们专注于与小胶质细胞密切相关的因素，并讨论它们在 AD 发病机制中的可能作用。此外，我们回顾了小胶质细胞的病理作用的最新观点，并强调了小胶质细胞对 Aβ 沉积的反应和表型变化的机制的重要性。重要的是，小胶质细胞激活的功能结果对神经元既有保护作用，也有损害作用。我们进一步描述了小胶质细胞在 tau 病理学和其他神经胶质细胞激活中的作用。通过这些主题，我们揭示了小胶质细胞作为 AD 和其他神经退行性疾病药物开发的有希望的靶点。
