Olufunmilayo Edward O, Holsinger R M Damian
Laboratory of Molecular Neuroscience and Dementia, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, NSW 2050 Australia; University College Hospital, Ibadan, Oyo State, Nigeria. Electronic address: https://twitter.com/@eddietobie.
Laboratory of Molecular Neuroscience and Dementia, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, NSW 2050 Australia; Neuroscience, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, NSW 2006 Australia.
J Mol Biol. 2022 Apr 15;434(7):167470. doi: 10.1016/j.jmb.2022.167470. Epub 2022 Feb 1.
Alzheimer's disease is the most common form of dementia, accounting for as much as three-quarters of cases globally with individuals in low- and middle-income countries being worst affected. Numerous risk factors for the disease have been identified and our understanding of gene-environment interactions have shed light on several gene variants that contribute to the most common, sporadic form of Alzheimer's disease. Triggering Receptor Expressed on Myeloid cells 2 (TREM2) is an important receptor that is crucial to the functioning of microglial cells, and variants of this protein have been found to be associated with a significantly increased risk of Alzheimer's disease. Several studies have elucidated the signaling processes involved in the normal functioning of the TREM2 receptor. However, current knowledge of the idiosyncrasies of the signaling processes triggered by stimulation of the variants of this receptor is limited. In this review, we examine the existing literature and highlight the effects that various receptor variants have on downstream signaling processes and discuss how these perturbations may affect physiologic processes in Alzheimer's disease. Despite the fact that this is a territory yet to be fully explored, the studies that currently exist report mostly quantitative effects on signaling. More mechanistic studies with the aim of providing qualitative results in terms of downstream signaling among these receptor variants are warranted. Such studies will provide better opportunities of identifying therapeutic targets that may be exploited in designing new drugs for the management of Alzheimer's disease.
阿尔茨海默病是最常见的痴呆形式，在全球病例中占多达四分之三，低收入和中等收入国家的个体受影响最为严重。已经确定了该疾病的众多风险因素，并且我们对基因-环境相互作用的理解揭示了几种导致最常见的散发性阿尔茨海默病的基因变体。髓系细胞触发受体2（TREM2）是一种重要的受体，对小胶质细胞的功能至关重要，并且已发现该蛋白的变体与阿尔茨海默病风险显著增加有关。多项研究阐明了TREM2受体正常功能所涉及的信号传导过程。然而，目前对于由该受体变体刺激引发的信号传导过程的特性的了解有限。在这篇综述中，我们研究了现有文献，强调了各种受体变体对下游信号传导过程的影响，并讨论了这些扰动如何可能影响阿尔茨海默病中的生理过程。尽管这是一个尚未完全探索的领域，但目前存在的研究大多报告了对信号传导的定量影响。有必要进行更多旨在提供这些受体变体之间下游信号传导定性结果的机制研究。此类研究将为识别可能用于设计治疗阿尔茨海默病新药的治疗靶点提供更好的机会。
