小胶质细胞通过触发髓样细胞 2 (TREM2) 上表达的受体吞噬营养不良的神经元，在突触消除中发挥至关重要的作用。它们还参与阿尔茨海默病 (AD) 中 β-淀粉样蛋白 (Aβ) 斑块的清除；尽管如此，TREM2 介导的 β-淀粉样蛋白 (Aβ) 斑块吞噬作用背后的驱动力仍然未知。在这里，使用先进的 2D/3D/4D 共培养系统，在 TREM2（外显子 2 中设计的移码突变）脑类器官/小胶质细胞/组合体中具有功能丧失突变，发现 Aβ 通过 TREM2 的清除速度加快由 Aβ 斑块周围的营养不良神经元产生的外化磷脂酰丝氨酸 (ePtdSer) 产生。此外，还研究了散发性（基于 CRISPR-Cas9 的 APOE4 系）和家族性（APPNL-G-F/MAPT 双敲入小鼠）AD 模型的小胶质细胞是否表现出 TREM2 水平降低以及对 ePtdSer 阳性 Aβ 的吞噬活性缺乏牌匾。本文提供了在 AD 进展过程中 ePtdSer 存在的背景下，TREM2 依赖性小胶质细胞对 Aβ 斑块的吞噬作用的新见解。© 2024 作者。 《Advanced Science》由 Wiley‐VCH GmbH 出版。

Microglia play a crucial role in synaptic elimination by engulfing dystrophic neurons via triggering receptors expressed on myeloid cells 2 (TREM2). They are also involved in the clearance of beta-amyloid (Aβ) plaques in Alzheimer's disease (AD); nonetheless, the driving force behind TREM2-mediated phagocytosis of beta-amyloid (Aβ) plaques remains unknown. Here, using advanced 2D/3D/4D co-culture systems with loss-of-function mutations in TREM2 (a frameshift mutation engineered in exon 2) brain organoids/microglia/assembloids, it is identified that the clearance of Aβ via TREM2 is accelerated by externalized phosphatidylserine (ePtdSer) generated from dystrophic neurons surrounding the Aβ plaques. Moreover, it is investigated whether microglia from both sporadic (CRISPR-Cas9-based APOE4 lines) and familial (APPNL-G-F/MAPT double knock-in mice) AD models show reduced levels of TREM2 and lack of phagocytic activity toward ePtdSer-positive Aβ plaques. Herein new insight is provided into TREM2-dependent microglial phagocytosis of Aβ plaques in the context of the presence of ePtdSer during AD progression.© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.