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A cell-autonomous role for border-associated macrophages in ApoE4 neurovascular dysfunction and susceptibility to
Antoine Anfray1, Samantha Schaeffer1, Yorito Hattori1
1Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
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.
Insights
Apolipoprotein E4 (ApoE4) in brain immune cells called border-associated macrophages (BAMs) drives neurovascular dysfunction and white matter injury, contributing to Alzheimer's disease risk.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Apolipoprotein E4 (ApoE4) is a major genetic risk factor for Alzheimer's disease (AD).
- ApoE4 is linked to cognitive impairment and microvascular pathologies, including white matter injury.
- The cellular origin and mechanisms of ApoE4's neurovascular effects remain largely unknown.
Purpose of the Study:
- To investigate the cellular source and mechanism of ApoE4-mediated neurovascular dysfunction.
- To elucidate the role of border-associated macrophages (BAMs) in ApoE4's pathological effects.
Main Methods:
- Utilized mouse models expressing human Apolipoprotein E3 (ApoE3) or ApoE4 (ApoE4).
- Examined the role of BAMs in mediating neurovascular dysfunction and white matter damage.
- Investigated the involvement of reactive oxygen species (ROS) in ApoE4's effects.
Main Results:
- Identified border-associated macrophages (BAMs) as a key source and effector of ApoE4.
- Demonstrated that ApoE4 in BAMs drives neurovascular dysfunction via reactive oxygen species (ROS).
- Showcased that BAM-derived ApoE4 is essential for white matter damage susceptibility in ApoE4 mice and exacerbates it in ApoE3 mice.
Conclusions:
- Border-associated macrophages (BAMs) play a critical cell-autonomous role in ApoE4-associated neurovascular dysfunction.
- BAM pathobiology offers new insights into Alzheimer's disease pathogenesis.
- Targeting BAMs presents a potential therapeutic strategy for ApoE4-related cognitive impairment.
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