Apolipoprotein E (APOE) controls cerebrovascular integrity via cyclophilin A (CypA). The study shows that APOE4, but not APOE2 or APOE3, leads to blood-brain barrier (BBB) breakdown by activating a proinflammatory CypA–nuclear factor-κB (NF-κB)–matrix-metalloproteinase-9 (MMP9) pathway in pericytes. This pathway causes neuronal uptake of blood-derived neurotoxic proteins and reduces microvascular and cerebral blood flow. Astrocyte-secreted APOE3, but not APOE4, suppresses this pathway through a lipoprotein receptor. The findings suggest that CypA is a key target for treating APOE4-mediated neurovascular injury and resulting neuronal dysfunction. APOE is a major genetic risk factor for Alzheimer's disease and is associated with Down's syndrome dementia and poor neurological outcomes after traumatic brain injury and hemorrhage. Neurovascular dysfunction is present in APOE4 carriers and individuals with APOE4-associated disorders. In mice, lack of ApoE leads to BBB breakdown, while APOE4 increases BBB susceptibility to injury. The study used various APOE transgenic mice, including those with CypA ablation or inhibition, to show that APOE4 and lack of murine ApoE, but not APOE2 or APOE3, lead to BBB breakdown. The study also found that APOE4 mice had increased CypA levels in cerebral microvessels, mainly due to increased CypA expression in pericytes. Cyclosporine A, which binds intracellular CypA and inhibits its effects, eliminated BBB disruption in APOE4 mice and neuronal accumulation of systemically administered cadaverine. These findings indicate that BBB changes are reversible and CypA can be therapeutically targeted to correct APOE4-induced BBB breakdown. The study also showed that APOE4 mice had numerous brain perivascular fibrin and haemosiderin foci, and elevated thrombin levels that were normalized with cyclosporine A. Thrombin is neurotoxic, fibrin accelerates neurovascular damage, and haemosiderin generates reactive oxygen species, implicating multiple potential BBB-derived sources of injury. The study further demonstrated that CypA activates NF-κB and the NF-κB–MMP9 pathway, leading to BBB breakdown. Inhibiting NF-κB or MMP9 activity reversed BBB disruption in APOE4 mice. The study also showed that APOE3, but not APOE4, regulates CypA through the low-density lipoprotein (LDL)/APOE receptor LRP1, which is required for APOE3-mediated inhibition of NF-κB-dependent MMP9 activationApolipoprotein E (APOE) controls cerebrovascular integrity via cyclophilin A (CypA). The study shows that APOE4, but not APOE2 or APOE3, leads to blood-brain barrier (BBB) breakdown by activating a proinflammatory CypA–nuclear factor-κB (NF-κB)–matrix-metalloproteinase-9 (MMP9) pathway in pericytes. This pathway causes neuronal uptake of blood-derived neurotoxic proteins and reduces microvascular and cerebral blood flow. Astrocyte-secreted APOE3, but not APOE4, suppresses this pathway through a lipoprotein receptor. The findings suggest that CypA is a key target for treating APOE4-mediated neurovascular injury and resulting neuronal dysfunction. APOE is a major genetic risk factor for Alzheimer's disease and is associated with Down's syndrome dementia and poor neurological outcomes after traumatic brain injury and hemorrhage. Neurovascular dysfunction is present in APOE4 carriers and individuals with APOE4-associated disorders. In mice, lack of ApoE leads to BBB breakdown, while APOE4 increases BBB susceptibility to injury. The study used various APOE transgenic mice, including those with CypA ablation or inhibition, to show that APOE4 and lack of murine ApoE, but not APOE2 or APOE3, lead to BBB breakdown. The study also found that APOE4 mice had increased CypA levels in cerebral microvessels, mainly due to increased CypA expression in pericytes. Cyclosporine A, which binds intracellular CypA and inhibits its effects, eliminated BBB disruption in APOE4 mice and neuronal accumulation of systemically administered cadaverine. These findings indicate that BBB changes are reversible and CypA can be therapeutically targeted to correct APOE4-induced BBB breakdown. The study also showed that APOE4 mice had numerous brain perivascular fibrin and haemosiderin foci, and elevated thrombin levels that were normalized with cyclosporine A. Thrombin is neurotoxic, fibrin accelerates neurovascular damage, and haemosiderin generates reactive oxygen species, implicating multiple potential BBB-derived sources of injury. The study further demonstrated that CypA activates NF-κB and the NF-κB–MMP9 pathway, leading to BBB breakdown. Inhibiting NF-κB or MMP9 activity reversed BBB disruption in APOE4 mice. The study also showed that APOE3, but not APOE4, regulates CypA through the low-density lipoprotein (LDL)/APOE receptor LRP1, which is required for APOE3-mediated inhibition of NF-κB-dependent MMP9 activation