APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer’s mice via cyclophilin A independently of amyloid-β

Apolipoprotein E4 (APOE4), the main susceptibility gene for Alzheimer’s disease (AD), leads to vascular dysfunction, amyloid-β pathology, neurodegeneration and dementia. How these different pathologies contribute to advanced-stage AD remains unclear. Using aged APOE knock-in mice crossed with 5xFAD mice, we show that, compared to APOE3, APOE4 accelerates blood–brain barrier (BBB) breakdown, loss of cerebral blood flow, neuronal loss and behavioral deficits independently of amyloid-β. BBB breakdown was associated with activation of the cyclophilin A-matrix metalloproteinase-9 BBB-degrading pathway in pericytes. Suppression of this pathway improved BBB integrity and prevented further neuronal loss and behavioral deficits in APOE4;5FAD mice while having no effect on amyloid-β pathology. Thus, APOE4 accelerates advanced-stage BBB breakdown and neurodegeneration in Alzheimer’s mice via the cyclophilin A pathway in pericytes independently of amyloid-β, which has implication for the pathogenesis and treatment of vascular and neurodegenerative disorder in AD. This study shows that APOE4, one of the largest genetic risk factors for Alzheimer’s disease, promotes advanced-stage vascular dysfunction and neurodegeneration in old mice via activation of the cyclophilin A pathway in pericytes and independently of the presence of amyloid-β.