Border-associated macrophages promote cerebral amyloid angiopathy and cognitive impairment through vascular oxidative stress

Abstract

Background Cerebral amyloid angiopathy (CAA) is a devastating condition common in patients with Alzheimer’s disease but also observed in the general population. Vascular oxidative stress and neurovascular dysfunction have been implicated in CAA but the cellular source of reactive oxygen species (ROS) and related signaling mechanisms remain unclear. We tested the hypothesis that brain border-associated macrophages (BAM), yolk sac-derived myeloid cells closely apposed to parenchymal and leptomeningeal blood vessels, are the source of radicals through the Aβ-binding innate immunity receptor CD36, leading to neurovascular dysfunction, CAA, and cognitive impairment. Methods Tg2576 mice and WT littermates were transplanted with CD36−/− or CD36+/+ bone marrow at 12-month of age and tested at 15 months. This approach enables the repopulation of perivascular and leptomeningeal compartments with CD36−/− BAM. Neurovascular function was tested in anesthetized mice equipped with a cranial window in which cerebral blood flow was monitored by laser-Doppler flowmetry. Amyloid pathology and cognitive function were also examined. Results The increase in blood flow evoked by whisker stimulation (functional hyperemia) or by endothelial and smooth muscle vasoactivity was markedly attenuated in WT → Tg2576 chimeras but was fully restored in CD36−/− → Tg2576 chimeras, in which BAM ROS production was suppressed. CAA-associated Aβ1-40, but not Aβ1-42, was reduced in CD36−/− → Tg2576 chimeras. Similarly, CAA, but not parenchymal plaques, was reduced in CD36−/− → Tg2576 chimeras. These beneficial vascular effects were associated with cognitive improvement. Finally, CD36−/− mice were able to more efficiently clear exogenous Aβ1-40 injected into the neocortex or the striatum. Conclusions CD36 deletion in BAM suppresses ROS production and rescues the neurovascular dysfunction and damage induced by Aβ. CD36 deletion in BAM also reduced brain Aβ1-40 and ameliorated CAA without affecting parenchyma plaques. Lack of CD36 enhanced the vascular clearance of exogenous Aβ. Restoration of neurovascular function and attenuation of CAA resulted in a near complete rescue of cognitive function. Collectively, these data implicate brain BAM in the pathogenesis of CAA and raise the possibility that targeting BAM CD36 is beneficial in CAA and other conditions associated with vascular Aβ deposition and damage. Graphical Abstract

Border-associated macrophages in the central nervous system

“…PVMs promote the expression of C1QA, GRN, and CTSB in microglia, leading to aberrant phagocytosis of neuronal synapses 4. PVMs may express APOE4, which is associated with neurovascular alterations and BBB breakdown [ 78 , 114 – 117 , 121 , 123 – 125 ] Parkinson’s Disease 1. α-Synuclein overexpression in transgenic mice 2. Human postmortem brain tissues 1.…”

“…Subsequently, it was discovered that PVMs contribute to Aβ-induced cerebrovascular oxidative stress by highly expressing the reactive oxygen species (ROS)-producing enzyme NOX2 and CD36, an Aβ-binding scavenger receptor [ 115 , 116 ]. In Tg2576 transgenic mice, a model of AD, the deletion of CD36 through PVM repopulation reduced ROS induction and ameliorated neurovascular damage induced by Aβ deposition [ 117 ]. Additionally, depleting PVMs with clodronate, a type of chemicals known as bisphosphonates, suppressed ROS production and alleviated Aβ-induced cerebrovascular dysfunction [ 118 ].…”

The contribution of β-amyloid, Tau and α-synuclein to blood–brain barrier damage in neurodegenerative disorders

“…Brain macrophages are essential sentinels in the immune response as they become activated under brain injury or immunological stimuli [ 47 ] and the resulting neuroinflammation can contribute to neurodegeneration both directly as well as by impairing the BBB [ 56 , 102 , 118 , 135 ]. Discerning the different roles of PvM Φ and vascular-associated microglia in BBB function has been challenging as they share cellular markers, such as Iba1 and CX3CR1, and produce similar inflammatory mediators.…”

“…Receptors like scavenger receptor (SR)-A, SR-BI and triggering receptor expressed on myeloid cells 2 promote the uptake of extracellular amyloid deposits without eliciting a significant inflammatory response, whereas TLR2/4 and CD36 stimulation induces the production of neurotoxic cytokines and ROS via nuclear factor κB (NFκB) and NLRP3-ASC-inflammasome pathways, thus promoting neuronal and vascular degeneration [ 54 , 64 , 131 ]. Reduction in SR-A and SR-BI impairs PvM Φ function and enhances CAA [ 83 , 131 ], while CD36 deficiency in PvM Φ is protective in transgenic mouse models [ 135 ].…”

Cerebral Amyloid Angiopathy

“…17,18 The implication of the central role of CAA is that ARIA might be avoided by improved CAA detection or mitigated by targeting key pathogenic mechanisms, such as activation of perivascular or border-associated macrophages. 19…”