McKee Chloe G, Hoffos Madison, Vecchiarelli Haley A, Tremblay Marie-Ève
Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.
Department of Biology, University of Victoria, Victoria, BC, Canada.
Front Pharmacol. 2023 Feb 9;14:1125982. doi: 10.3389/fphar.2023.1125982. eCollection 2023.
As individuals age, microglia, the resident immune cells of the central nervous system (CNS), become less effective at preserving brain circuits. Increases in microglial inflammatory activity are thought to contribute to age-related declines in cognitive functions and to transitions toward mild cognitive impairment (MCI) and Alzheimer's disease (AD). As microglia possess receptors for communicating with the CNS environment, pharmacological therapies targeting these pathways hold potential for promoting homeostatic microglial functions within the aging CNS. Preclinical and early phase clinical trials investigating the therapeutic effects of pharmacological agents acting on microglia, including reactive oxygen species, TREM2, fractalkine signaling, the complement cascade, and the NLRP3 inflammasome, are currently underway; however, important questions remain unanswered. Current challenges include target selectivity, as many of the signaling pathways are expressed in other cell types. Furthermore, microglia are a heterogenous cell population with transcriptomic, proteomic, and microscopy studies revealing distinct microglial states, whose activities and abundance shift across the lifespan. For example, homeostatic microglia can transform into pathological states characterized by markers of oxidative stress. Selective pharmacological targeting aimed at limiting transitions to pathological states or promoting homeostatic or protective states, could help to avoid potentially harmful off-target effects on beneficial states or other cell types. In this mini-review we cover current microglial pathways of interest for the prevention and treatment of age-related cognitive decline and CNS disorders of aging focusing on MCI and AD. We also discuss the heterogeneity of microglia described in these conditions and how pharmacological agents could target specific microglial states.
随着个体年龄的增长，作为中枢神经系统（CNS）固有免疫细胞的小胶质细胞，在保护脑回路方面的作用变得越来越弱。小胶质细胞炎症活性的增加被认为与认知功能的年龄相关性下降以及向轻度认知障碍（MCI）和阿尔茨海默病（AD）的转变有关。由于小胶质细胞具有与中枢神经系统环境进行通讯的受体，针对这些途径的药物疗法有望促进衰老中枢神经系统内小胶质细胞的稳态功能。目前正在进行临床前和早期临床试验，研究作用于小胶质细胞的药物的治疗效果，这些药物包括活性氧、触发受体表达于髓系细胞2（TREM2）、 fractalkine信号传导、补体级联反应和NLRP3炎性小体；然而，一些重要问题仍未得到解答。当前的挑战包括靶点选择性，因为许多信号通路在其他细胞类型中也有表达。此外，小胶质细胞是一个异质性细胞群体，转录组学、蛋白质组学和显微镜研究揭示了不同的小胶质细胞状态，其活性和丰度在整个生命周期中都会发生变化。例如，稳态小胶质细胞可以转变为以氧化应激标志物为特征的病理状态。旨在限制向病理状态转变或促进稳态或保护状态的选择性药物靶向治疗，有助于避免对有益状态或其他细胞类型产生潜在有害的脱靶效应。在这篇小型综述中，我们涵盖了目前对于预防和治疗与年龄相关的认知衰退以及衰老相关的中枢神经系统疾病（重点是MCI和AD）具有重要意义的小胶质细胞途径。我们还讨论了在这些情况下所描述的小胶质细胞的异质性，以及药物如何靶向特定的小胶质细胞状态。
