Cell autonomous role of border associated macrophages in ApoE4 neurovascular dysfunction and susceptibility to white matter injury

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 (BAM), myeloid cells closely apposed to neocortical microvessels, are both the source and the target of the ApoE4 mediating the neurovascular dysfunction through reactive oxygen species. ApoE4 in BAM 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.

Lipid-siRNA conjugate accesses a perivascular transport mechanism and achieves widespread and durable knockdown in the central nervous system

“…We were also interested in targeting of border-associated macrophages as they are key players in a myriad of CNS disorders, including driving neurovascular dysfunction in hypertension and Alzheimer’s disease. 53,54 One recent study identified two subtypes of macrophages, Lyve1+ and MHCII+, and demonstrated that Lyve1+ macrophages decrease with age leading to impaired CSF dynamics that can be restored with administration of macrophage colony-stimulating factor (M-CSF). 42 MHCII+ BAMs are also implicated in neurodegeneration, for example by initiating α-synuclein-mediated neuroinflammatory responses through restimulation of CD4+ T-cells.…”

Three major effects of APOEε4 on Aβ immunotherapy induced ARIA

“…New studies in mouse models suggest APOE ε4 driven neurovascular uncoupling, with APOE ε3/ε4 mice and APOE ε4/ε4 mice showing differential cerebral perfusion and glucose uptake ( Onos et al, 2023 ). Further, boarder association macrophages (BAMs) have been shown to provide APOE ε4 to a detrimental effect to the neurovascular unit ( Iadecola et al, 2023 ). When APOE is knocked out of BAM cells specifically, function of the neurovascular unit is rescued, providing another cell type and mechanism by which APOE regulates NVU integrity.…”