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Here, we combined spatiotemporal single\u2010cell and single\u2010nucleus transcriptomics in APP23 mice with mechanistic studies in human brain endothelial cells and validation in human CAA\u2010related hemorrhagic tissues to define the endothelial stress pathways driving disease progression. Endothelial cells emerged as an early and highly vulnerable vascular population during CAA development, characterized by persistent activation of endoplasmic reticulum (ER) stress programs with preferential engagement of the IRE1\u03b1 branch. In vitro, A\u03b240 preformed fibrils directly induced ER remodeling, aberrant solid\u2010like phase transition of GRP78, sustained IRE1\u03b1\u2013TRAF2\u2013JNK signaling, endothelial apoptosis, and tight junction loss. In vivo, pharmacological inhibition of IRE1\u03b1 with 4\u00b58C restored junctional integrity, reduced blood\u2010brain barrier leakage, attenuated vascular amyloid pathology, and improved behavioral performance. Human CAA\u2010related intracerebral hemorrhage specimens recapitulated endothelial ER stress, apoptotic activation, and tight junction depletion. These findings identify persistent endothelial IRE1\u03b1 signaling as a key driver of cerebrovascular failure in CAA, highlighting its potential as a therapeutic target for vascular amyloidosis.<\/jats:p>","DOI":"10.1002\/advs.76761","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T12:27:22Z","timestamp":1784896042000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Aberrant GRP78 Phase Transition Sustains Endothelial IRE1\u03b1 Signaling and Drives Blood\u2013Brain Barrier Failure in Cerebral Amyloid Angiopathy"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-1002-6761","authenticated-orcid":false,"given":"Honglin","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Neurology the First Affiliated Hospital of Zhengzhou University Zhengzhou University  Zhengzhou Henan 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