Recent genetic studies have provided overwhelming evidence of the involvement of microglia-related molecular networks in the pathophysiology of Alzheimer's disease (AD). However, the precise mechanisms by which microglia alter the course of AD neuropathology remain poorly understood. Here we discuss current evidence of the neuroprotective functions of microglia with a focus on optical imaging studies that have revealed a role of these cells in the encapsulation of amyloid deposits ("microglia barrier"). This barrier modulates the degree of plaque compaction, amyloid fibril surface area, and insulation from adjacent axons thereby reducing neurotoxicity. We discuss findings implicating genetic variants of the microglia receptor, triggering receptor expressed on myeloid cells 2, in the increased risk of late onset AD. We provide evidence that increased AD risk may be at least partly mediated by deficient microglia polarization toward amyloid deposits, resulting in ineffective plaque encapsulation and reduced plaque compaction, which is associated with worsened axonal pathology. Finally, we propose possible avenues for therapeutic targeting of plaque-associated microglia with the goal of enhancing the microglia barrier and potentially reducing disease progression.

中文翻译：

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小胶质细胞介导的神经保护、TREM2 和阿尔茨海默病：来自光学成像的证据

最近的遗传研究提供了压倒性的证据，证明小胶质细胞相关分子网络参与阿尔茨海默病 (AD) 的病理生理学。然而，小胶质细胞改变 AD 神经病理学过程的确切机制仍然知之甚少。在这里，我们讨论了小胶质细胞神经保护功能的当前证据，重点是光学成像研究，这些研究揭示了这些细胞在包裹淀粉样蛋白沉积物（“小胶质细胞屏障”）中的作用。该屏障调节斑块压实程度、淀粉样原纤维表面积和与相邻轴突的绝缘，从而降低神经毒性。我们讨论了与小胶质细胞受体遗传变异相关的发现，触发骨髓细胞上表达的受体 2，与晚发性 AD 风险增加有关。我们提供的证据表明，AD 风险的增加可能至少部分是由小胶质细胞向淀粉样沉积物的极化不足引起的，导致无效的斑块包封和斑块压实减少，这与轴突病理恶化有关。最后，我们提出了针对斑块相关小胶质细胞的治疗靶向的可能途径，目的是增强小胶质细胞屏障并可能减少疾病进展。