Endothelial BACE1 impairs insulin signaling to drive cerebral small vessel disease and stroke

Cerebral small vessel disease (CSVD) is a major cause of stroke and dementia, yet its molecular etiology remains incompletely understood, and no disease-modifying therapies are currently available. Here, we identify a non-canonical pathogenic mechanism linking β-secretase 1 (BACE1), a therapeutic target for Alzheimer's disease, to vascular insulin resistance. BACE1 was upregulated in the cerebral endothelium of patients with hypertensive arteriopathy and cerebral amyloid angiopathy. The upregulated endothelial BACE1 cleaved the β-subunit of insulin receptor (INSR), disrupting the INSR-Akt-endothelial nitric oxide synthase (eNOS) signaling axis required for vascular homeostasis. This disruption occurred early in disease progression in a relevant rodent model of CSVD, the stroke-prone spontaneously hypertensive rat fed a high-salt diet. Treatment with the clinical BACE1 inhibitor elenbecestat (E2609) restored endothelial function, ameliorated cerebrovascular pathology, and significantly reduced stroke incidence. INSR blockade abolished these protective effects, supporting an INSR-dependent mechanism. These findings identify an intersection between neurodegenerative and metabolic pathways in the vasculature and suggest that BACE1 inhibitors, previously abandoned in Alzheimer's disease treatment, may have therapeutic potential for stroke prevention and CSVD therapy.