Hemonnot Anne-Laure, Hua Jennifer, Ulmann Lauriane, Hirbec Hélène
Institute for Functional Genomics (IGF), University of Montpellier, Centre National de la Recherche Scientififique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France.
Front Aging Neurosci. 2019 Aug 30;11:233. doi: 10.3389/fnagi.2019.00233. eCollection 2019.
Microglia are the resident macrophages of the central nervous system. They play key roles in brain development, and physiology during life and aging. Equipped with a variety of molecular sensors and through the various functions they can fulfill, they are critically involved in maintaining the brain's homeostasis. In Alzheimer disease (AD), microglia reaction was initially thought to be incidental and triggered by amyloid deposits and dystrophic neurites. However, recent genome-wide association studies have established that the majority of AD risk loci are found in or near genes that are highly and sometimes uniquely expressed in microglia. This leads to the concept of microglia being critically involved in the early steps of the disease and identified them as important potential therapeutic targets. Whether microglia reaction is beneficial, detrimental or both to AD progression is still unclear and the subject of intense debate. In this review, we are presenting a state-of-knowledge report intended to highlight the variety of microglial functions and pathways shown to be critically involved in AD progression. We first address both the acquisition of new functions and the alteration of their homeostatic roles by reactive microglia. Second, we propose a summary of new important parameters currently emerging in the field that need to be considered to identify relevant microglial targets. Finally, we discuss the many obstacles in designing efficient therapeutic strategies for AD and present innovative technologies that may foster our understanding of microglia roles in the pathology. Ultimately, this work aims to fly over various microglial functions to make a general and reliable report of the current knowledge regarding microglia's involvement in AD and of the new research opportunities in the field.
小胶质细胞是中枢神经系统中的常驻巨噬细胞。它们在大脑发育以及生命和衰老过程中的生理活动中发挥着关键作用。小胶质细胞配备有多种分子传感器，并通过其能够实现的各种功能，在维持大脑的内环境稳定方面发挥着至关重要的作用。在阿尔茨海默病（AD）中，小胶质细胞反应最初被认为是偶然的，由淀粉样蛋白沉积物和营养不良性神经突引发。然而，最近的全基因组关联研究表明，大多数AD风险基因座位于小胶质细胞中高度表达甚至有时独特表达的基因内或其附近。这引出了小胶质细胞在疾病早期阶段起关键作用的概念，并将它们确定为重要的潜在治疗靶点。小胶质细胞反应对AD进展是有益、有害还是两者皆有，目前仍不清楚，并且是激烈辩论的主题。在本综述中，我们呈现一份知识现状报告，旨在突出已显示与AD进展密切相关的各种小胶质细胞功能和途径。我们首先探讨反应性小胶质细胞新功能的获得及其稳态作用的改变。其次，我们总结该领域目前出现的新的重要参数，这些参数在确定相关的小胶质细胞靶点时需要考虑。最后，我们讨论在设计AD有效治疗策略时存在的诸多障碍，并介绍可能增进我们对小胶质细胞在病理学中作用理解的创新技术。最终，这项工作旨在梳理各种小胶质细胞功能，就目前关于小胶质细胞参与AD的知识以及该领域的新研究机会做出全面且可靠的报告。
