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

被引：7

作者：

Anfray, Antoine ^{[1
]}

Schaeffer, Samantha ^{[1
]}

Hattori, Yorito ^{[1
]}

Santisteban, Monica M. ^{[1
]}

Casey, Nicole ^{[1
]}

Wang, Gang ^{[1
]}

Strickland, Michael ^{[2
]}

Zhou, Ping ^{[1
]}

Holtzman, David M. ^{[2
]}

Anrather, Josef ^{[1
]}

Park, Laibaik ^{[1
]}

Iadecola, Costantino ^{[1
]}

机构：

[1] Weill Cornell Med, Feil Family Brain & Mind Res Inst, New York, NY 10021 USA

[2] Washington Univ, Charles F & Joanne Knight Alzheimers Dis Res Ctr, Hope Ctr Neurol Disorders, Sch Med,Dept Neurol, St Louis, MO USA

来源：

NATURE NEUROSCIENCE | 2024年 / 27卷 / 11期

基金：

美国国家卫生研究院;

关键词：

APOLIPOPROTEIN-E GENE; CEREBRAL-BLOOD-FLOW; COGNITIVE IMPAIRMENT; ALZHEIMER-DISEASE; ANGIOTENSIN-II; NITRIC-OXIDE; MOUSE; ACCUMULATION; MICROGLIA; MEDIATE;

D O I：

10.1038/s41593-024-01757-6

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：2138 / 2151

页数：36