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Nat. Neurosci., Sep 18 2024, | https://doi.org/10.1038/s41593-024-01757-6
A cell-autonomous role for border-associated macrophages in ApoE4 neurovascular dysfunction and susceptibility to white matter injury
Antoine Anfray1, Samantha Schaeffer1, Yorito Hattori1, Monica M. Santisteban1, Nicole Casey1, Gang Wang1, Michael Strickland2, Ping Zhou1, David M. Holtzman2, Josef Anrather1, Laibaik Park1 & Costantino Iadecola1
1Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
2Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.
Corresponding authors
Correspondence to Laibaik Park or Costantino Iadecola.
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.
논문정보
- Research article
- 2024년 09월 (BRIC 등록일 2025-01-22)
- 국외 연구진
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