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bioRxiv · 10.64898/2026.10.13.758947

Endothelial CD36 links arteriolar remodeling to metabolic and immune alterations in Alzheimer's disease

Kumar, A.·Zhang, J.·Harvey, J.·Guenter, R.·Chkheidze, R.·Sethu, P.·Beck, A. W.·Ren, B.
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Abstract

Alzheimer's disease (AD) is accompanied by profound cerebrovascular dysfunction, yet it remains unclear whether endothelial abnormalities reflect only vascular injury or altered regulatory states connecting vascular remodeling with metabolic and immune function. We integrated human brain transcriptomic and histopathological data with complementary mouse genetic and human iPSC-derived endothelial models to examine a CD36-centered endothelial-state framework in AD. Analysis of the Seattle Alzheimer's Disease Brain Cell Atlas identified three CD36-expressing endothelial populations; intermediate-CD36 Endo 2 predominated in both reference and AD samples, although the relative subset distributions differed. In hippocampal and cortical tissue from six AD patients, endothelial CD36 expression was observed in structurally abnormal arterioles with disrupted mural organization. In complementary mouse studies, endothelial PKD1 deficiency was accompanied by increased vascular CD36 and cerebrovascular abnormalities, whereas endothelial CD36 deletion altered lipid-metabolic and innate-immune-associated transcriptional programs, including AD-relevant genes and pathways, under metabolic-inflammatory stress. To assess whether distinct human endothelial backgrounds remained pharmacologically responsive, we treated control and CRISPR-engineered PSEN1 E276A iPSC-derived ECs with GS4898, a small molecule previously linked to arterial specification. Both maintained endothelial identity but displayed different baseline transcriptional profiles and shared as well as cell-line-dependent responses to GS4898. Together, our study identifies a CD36-associated vascular phenotype in human AD, demonstrates CD36-dependent regulation of brain endothelial metabolic-immune transcriptional programs in vivo, and reveals endothelial transcriptional responsiveness to pharmacologic perturbation. The observed endothelial transcriptional plasticity may provide a basis for developing state-selective therapeutic strategies targeting cerebrovascular dysfunction in AD.

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Kumar, A., Zhang, J., Harvey, J., Guenter, R., Chkheidze, R., Sethu, P., Beck, A. W., Ren, B.. 2026-10-14. Endothelial CD36 links arteriolar remodeling to metabolic and immune alterations in Alzheimer's disease. https://doi.org/10.64898/2026.10.13.758947

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