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

TitleBorder-associated macrophages promote cerebral amyloid angiopathy and cognitive impairment through vascular oxidative stress.
Publication TypeJournal Article
Year of Publication2023
AuthorsUekawa K, Hattori Y, Ahn SJi, Seo J, Casey N, Anfray A, Zhou P, Luo W, Anrather J, Park L, Iadecola C
JournalMol Neurodegener
Date Published2023 Oct 03
KeywordsAlzheimer Disease, Amyloid beta-Peptides, Animals, Brain, Cerebral Amyloid Angiopathy, Cognitive Dysfunction, Humans, Macrophages, Mice, Mice, Transgenic, Oxidative Stress, Reactive Oxygen Species

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.

Alternate JournalMol Neurodegener
PubMed ID37789345
PubMed Central IDPMC10548599
Grant ListR01 NS037853 / NS / NINDS NIH HHS / United States
R01 NS097805 / NS / NINDS NIH HHS / United States
NS37853 / NH / NIH HHS / United States