CAA is an age-related cerebral small vessel disease (CSVD) defined by β-amyloid (Aβ) deposition in cortical and leptomeningeal vessels. The integrity of both the structure and function of the neurovascular unit is critical for the efficient clearance of excess Aβ accumulated in the brain. Characteristics of cerebrovascular cells in CAA remain poorly understood at single-cell resolution due to their sparsity and dispersion.

To investigate the single-cell transcriptome profile of cerebral microvessels in the early stage of cerebral amyloid angiopathy (CAA).

Purified microvessels from the cerebral cortex of three groups of 11-month-old male APP23 transgenic mice and age- and sex-matched wild-type C57BL6J mice were collected for single-cell RNA sequencing (scRNA-seq) analysis. Our findings were verified using western blotting and immunofluorescence.

A total of ~26,000 cerebrovascular cells across 8 subtypes were captured, categorized into three meta clusters, including endothelial cells (arteries, veins and capillaries), mural cells (smooth muscle cells and pericytes), and immune cells (microglia, monocytes and B/NK cells). Endothelial cells (ECs) were particularly decreased in the APP23-Tg group. Functional enrichment analysis indicated the exclusively activated ferroptosis in venous ECs, especially in the APP23-Tg group. Western blotting and immunofluorescence further validated our findings. Intercellular communication network indicated the intense crosstalk between venous ECs and microglia. Mechanically, elevated Il1b from microglia binds to the Il1r1 of venous ECs in the APP23-Tg group to stimulate the downstream NF-κB signaling pathway, leading to ferroptosis of venous ECs.