TY - JOUR
T1 - A cell-autonomous role for border-associated macrophages in ApoE4 neurovascular dysfunction and susceptibility to white matter injury
AU - Anfray, Antoine
AU - Schaeffer, Samantha
AU - Hattori, Yorito
AU - Santisteban, Monica M.
AU - Casey, Nicole
AU - Wang, Gang
AU - Strickland, Michael
AU - Zhou, Ping
AU - Holtzman, David M.
AU - Anrather, Josef
AU - Park, Laibaik
AU - Iadecola, Costantino
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.
PY - 2024/11
Y1 - 2024/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85204310975&partnerID=8YFLogxK
U2 - 10.1038/s41593-024-01757-6
DO - 10.1038/s41593-024-01757-6
M3 - Article
C2 - 39294490
AN - SCOPUS:85204310975
SN - 1097-6256
VL - 27
SP - 2138
EP - 2151
JO - Nature neuroscience
JF - Nature neuroscience
IS - 11
ER -