美国威尔康奈尔医学院Costantino Iadecola等合作研究团队近日取得一项新成果。经过不懈努力，他们的最新研究提出了边界相关巨噬细胞在ApoE4引起的神经血管功能障碍和易感白质损伤中的自主作用。2024年9月18日出版的《自然—神经科学》杂志发表了这项成果。

在表达人类ApoE3或ApoE4的小鼠中，发现边界相关巨噬细胞（BAMs），即紧贴新皮质微血管的髓系细胞，既是ApoE4的来源，又是其效应者，通过活性氧（ROS）介导神经血管功能障碍。在ApoE4小鼠中，BAMs中的ApoE4完全负责增加对寡缺性白质损伤的易感性，并且足以增强ApoE3小鼠的损伤。

这些数据揭示了BAM病理生物学的一个新方面，并强调了以前未被认识到的BAM在ApoE4神经血管功能障碍中的细胞自主作用，具有潜在的治疗意义。

研究人员表示，载脂蛋白E4 (ApoE4)是散发性阿尔茨海默病最强的遗传危险因素，也是微血管病变导致认知障碍，特别是皮质下白质损伤的危险因素。这些影响被归因于脑供血调节的改变，但ApoE4的细胞来源及其潜在机制尚不清楚。

附：英文原文

Title: A cell-autonomous role for border-associated macrophages in ApoE4 neurovascular dysfunction and susceptibility to white matter injury

Author: Anfray, Antoine, Schaeffer, Samantha, Hattori, Yorito, Santisteban, Monica M., Casey, Nicole, Wang, Gang, Strickland, Michael, Zhou, Ping, Holtzman, David M., Anrather, Josef, Park, Laibaik, Iadecola, Costantino

Issue&Volume: 2024-09-18

Abstract: Apolipoprotein E4 (ApoE4), the strongest genetic risk factor for sporadic Alzheimer’s disease, is also a risk factor for microvascular pathologies leading to cognitive impairment, particularly subcortical white matter injury. These effects have been attributed to alterations in the regulation of the brain blood supply, but the cellular source of ApoE4 and the underlying mechanisms remain unclear. In mice expressing human ApoE3 or ApoE4, we report that border-associated macrophages (BAMs), myeloid cells closely apposed to neocortical microvessels, are both sources and effectors of ApoE4 mediating the neurovascular dysfunction through reactive oxygen species. ApoE4 in BAMs is solely responsible for the increased susceptibility to oligemic white matter damage in ApoE4 mice and is sufficient to enhance damage in ApoE3 mice. The data unveil a new aspect of BAM pathobiology and highlight a previously unrecognized cell-autonomous role of BAM in the neurovascular dysfunction of ApoE4 with potential therapeutic implications.

DOI: 10.1038/s41593-024-01757-6

Source: https://www.nature.com/articles/s41593-024-01757-6