Aberrant GRP78 Phase Transition Sustains Endothelial IRE1α Signaling and Drives Blood–Brain Barrier Failure in Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) is a major cause of vascular cognitive impairment and lobar intracerebral hemorrhage, yet the mechanisms by which vascular amyloid-beta (Aβ) disrupts cerebrovascular integrity remain poorly defined. Here, we combined spatiotemporal single-cell and single-nucleus transcriptomics in APP23 mice with mechanistic studies in human brain endothelial cells and validation in human CAA-related 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 IRE1α branch. In vitro, Aβ40 preformed fibrils directly induced ER remodeling, aberrant solid-like phase transition of GRP78, sustained IRE1α-TRAF2-JNK signaling, endothelial apoptosis, and tight junction loss. In vivo, pharmacological inhibition of IRE1α with 4µ8C restored junctional integrity, reduced blood-brain barrier leakage, attenuated vascular amyloid pathology, and improved behavioral performance. Human CAA-related intracerebral hemorrhage specimens recapitulated endothelial ER stress, apoptotic activation, and tight junction depletion. These findings identify persistent endothelial IRE1α signaling as a key driver of cerebrovascular failure in CAA, highlighting its potential as a therapeutic target for vascular amyloidosis.