Kwon Hyo Jun, Santhosh Devi, Huang Zhen
Departments of Neurology and Neuroscience, University of Wisconsin-Madison, Madison, United States.
Elife. 2024 Dec 5;13:RP100446. doi: 10.7554/eLife.100446.
Amyloid β (Aβ) forms aggregates in the Alzheimer's disease brain and is well known for its pathological roles. Recent studies show that it also regulates neuronal physiology in the healthy brain. Whether Aβ also regulates glial physiology in the normal brain, however, has remained unclear. In this article, we describe the discovery of a novel signaling pathway activated by the monomeric form of Aβ in vitro that plays essential roles in the regulation of microglial activity and the assembly of neocortex during mouse development in vivo. We find that activation of this pathway depends on the function of amyloid precursor and the heterotrimeric G protein regulator Ric8a in microglia and inhibits microglial immune activation at transcriptional and post-transcriptional levels. Genetic disruption of this pathway during neocortical development results in microglial dysregulation and excessive matrix proteinase activation, leading to basement membrane degradation, neuronal ectopia, and laminar disruption. These results uncover a previously unknown function of Aβ as a negative regulator of brain microglia and substantially elucidate the underlying molecular mechanisms. Considering the prominence of Aβ and neuroinflammation in the pathology of Alzheimer's disease, they also highlight a potentially overlooked role of Aβ monomer depletion in the development of the disease.
淀粉样β蛋白（Aβ）在阿尔茨海默病患者的大脑中形成聚集体，并因其病理作用而广为人知。最近的研究表明，它在健康大脑中也调节神经元生理功能。然而，Aβ在正常大脑中是否也调节神经胶质细胞生理功能仍不清楚。在本文中，我们描述了在体外由Aβ单体形式激活的一种新型信号通路的发现，该通路在体内小鼠发育过程中对小胶质细胞活性的调节和新皮质的组装起着重要作用。我们发现该通路的激活依赖于淀粉样前体蛋白的功能以及小胶质细胞中异三聚体G蛋白调节剂Ric8a的功能，并在转录和转录后水平抑制小胶质细胞的免疫激活。在新皮质发育过程中该通路的基因破坏导致小胶质细胞失调和基质蛋白酶过度激活，从而导致基底膜降解、神经元异位和层状破坏。这些结果揭示了Aβ作为脑小胶质细胞负调节因子的一个以前未知的功能，并 substantially阐明了潜在的分子机制。考虑到Aβ和神经炎症在阿尔茨海默病病理学中的突出地位，它们还突出了Aβ单体消耗在该疾病发展中一个可能被忽视的作用。 （注：原文中“substantially”直译为“实质上”，放在此处语义稍显不通顺，推测可能是拼写错误，也许是“substantially”，但不影响整体理解，故保留原文翻译。）
