Aβ1-40 induces venular endothelial cell ferroptosis in cerebral amyloid angiopathy via the ATF3/xCT axis: Insights from single-cell RNA sequencing.

introductionAmyloid-beta (Aβ)-induced microvascular injury is a key pathological feature of cerebral amyloid angiopathy (CAA). Recent evidence suggests that ferroptosis is implicated in Aβ pathology; however, its cell-type specificity and regulatory mechanisms within the cerebral microvasculature in CAA remain unclear.

methodsSingle-cell RNA sequencing (scRNA-seq) was performed on cortical microvessels from 11-month-old APP23 mice and wild-type littermates to identify cell-type-specific ferroptosis signatures. Biochemical, histopathological, and intervention experiments were further conducted to validate the findings and investigate the underlying mechanisms.

resultsVenous endothelial cluster exhibited the most prominent enrichment of ferroptosis signatures in scRNA-seq analysis, with subsequent experiments demonstrating progressive ferroptosis-related alterations in cortical venular endothelial cells (vECs) during CAA development. Mechanistically, Aβ1-40 increased activating transcription factor 3 (ATF3) expression and its occupancy at the Slc7a11 promoter, whereas ATF3 silencing restored Slc7a11/xCT expression, supporting ATF3-mediated Slc7a11/xCT repression and consequent impairment of glutathione-dependent antioxidant defense. Importantly, endothelial ATF3 knockdown attenuated ferroptosis-related alterations in vECs, reduced cerebral Aβ burden, and ameliorated cognitive deficits in APP23 mice. DISCUSSION: This study uncovers a previously underrecognized Aβ-driven microvascular injury characterized by vEC ferroptosis and highlights the ATF3/xCT axis as a potential therapeutic target in the early stage of CAA.