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Recent evidence suggests that ferroptosis is implicated in A\u03b2 pathology; however, its cell\u2010type specificity and regulatory mechanisms within the cerebral microvasculature in CAA remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>Single\u2010cell RNA sequencing (scRNA\u2010seq) was performed on cortical microvessels from 11\u2010month\u2010old APP23 mice and wild\u2010type littermates to identify cell\u2010type\u2010specific ferroptosis signatures. Biochemical, histopathological, and intervention experiments were further conducted to validate the findings and investigate the underlying mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Venous endothelial cluster exhibited the most prominent enrichment of ferroptosis signatures in scRNA\u2010seq analysis, with subsequent experiments demonstrating progressive ferroptosis\u2010related alterations in cortical venular endothelial cells (vECs) during CAA development. Mechanistically, A\u03b21\u201040 increased activating transcription factor 3 (ATF3) expression and its occupancy at the\n                      <jats:italic>Slc7a11<\/jats:italic>\n                      promoter, whereas ATF3 silencing restored\n                      <jats:italic>Slc7a11<\/jats:italic>\n                      \/xCT expression, supporting ATF3\u2010mediated\n                      <jats:italic>Slc7a11\/<\/jats:italic>\n                      xCT repression and consequent impairment of glutathione\u2010dependent antioxidant defense. Importantly, endothelial ATF3 knockdown attenuated ferroptosis\u2010related alterations in vECs, reduced cerebral A\u03b2 burden, and ameliorated cognitive deficits in APP23 mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>DISCUSSION<\/jats:title>\n                    <jats:p>This study uncovers a previously underrecognized A\u03b2\u2010driven microvascular injury characterized by vEC ferroptosis and highlights the ATF3\/xCT axis as a potential therapeutic target in the early stage of CAA.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/alz.71858","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T04:22:13Z","timestamp":1789964533000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A\u03b21\u201040 induces venular endothelial cell ferroptosis in cerebral amyloid angiopathy via the ATF3\/xCT axis: Insights from single\u2010cell RNA sequencing"],"prefix":"10.1002","volume":"22","author":[{"given":"Chunmei","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Neurology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology; Hubei Key Laboratory of Neural Injury and Functional Reconstruction Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Neurology Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hualin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Geriatrics Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology  Wuhan 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Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruizhi","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Neurology Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suiqiang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Neurology Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology  Wuhan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanshan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Neurology Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology  Wuhan 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