Recent genetic studies on Alzheimer’s disease (AD) have brought microglia under the spotlight, as loci associated with AD risk are enriched in genes expressed in microglia. Several of these genes have been recognized for their central roles in microglial functions. Increasing evidence suggests that SHIP1, the protein encoded by the AD-associated gene INPP5D, is an important regulator of microglial phagocytosis and immune response. A recent study from our group identified SHIP1 as a negative regulator of the NLRP3 inflammasome in human iPSC-derived microglial cells (iMGs). In addition, we found evidence for a connection between SHIP1 activity and inflammasome activation in the AD brain. The NLRP3 inflammasome is a multiprotein complex that induces the secretion of pro-inflammatory cytokines as part of innate immune responses against pathogens and endogenous damage signals. Previously published studies have suggested that the NLRP3 inflammasome is activated in AD and contributes to AD-related pathology. Here, we provide an overview of the current understanding of the microglial NLRP3 inflammasome in the context of AD-related inflammation. We then review the known intracellular functions of SHIP1, including its role in phosphoinositide signaling, interactions with microglial phagocytic receptors such as TREM2 and evidence for its intersection with NLRP3 inflammasome signaling. Through rigorous examination of the intricate connections between microglial signaling pathways across several experimental systems and postmortem analyses, the field will be better equipped to tailor newly emerging therapeutic strategies targeting microglia in neurodegenerative diseases.

中文翻译：

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小胶质细胞功能、INPP5D/SHIP1 信号传导和 NLRP3 炎性体激活：对阿尔茨海默病的影响

最近关于阿尔茨海默病 (AD) 的遗传学研究使小胶质细胞成为人们关注的焦点，因为与 AD 风险相关的位点在小胶质细胞中表达的基因中丰富。其中一些基因已被认为在小胶质细胞功能中发挥着核心作用。越来越多的证据表明，由 AD 相关基因 INPP5D 编码的蛋白质 SHIP1 是小胶质细胞吞噬作用和免疫反应的重要调节因子。我们小组最近的一项研究发现，SHIP1 是人 iPSC 衍生的小胶质细胞 (iMG) 中 NLRP3 炎症小体的负调节因子。此外，我们还发现了 AD 大脑中 SHIP1 活性与炎症小体激活之间存在联系的证据。NLRP3 炎症小体是一种多蛋白复合物，可诱导促炎细胞因子的分泌，作为针对病原体和内源性损伤信号的先天免疫反应的一部分。先前发表的研究表明，NLRP3 炎症小体在 AD 中被激活，并导致 AD 相关病理。在这里，我们概述了目前对 AD 相关炎症背景下小胶质细胞 NLRP3 炎症小体的理解。然后，我们回顾了 SHIP1 已知的细胞内功能，包括其在磷酸肌醇信号传导中的作用、与小胶质细胞吞噬受体（如 TREM2）的相互作用以及其与 NLRP3 炎性体信号传导交叉的证据。通过对多个实验系统中小胶质细胞信号通路之间复杂的联系进行严格检查和事后分析，该领域将能够更好地制定针对神经退行性疾病中小胶质细胞的新兴治疗策略。