APOE4 impairs blood-brain barrier via cyclophilin A

APOE4, a form of the human apolipoprotein E gene, is a genetic risk factor for Alzheimer’s disease (AD) and is also associated with other forms of neuropathology. APOE4 is thought to compromise the blood-brain barrier (BBB), but the underlying mechanisms have been unclear. Bell et al. addressed this issue by studying the brain microvasculature in several strains of genetically engineered mice: one lacking the mouse Apoe gene, and others expressing human APOE2, APOE3 or APOE4. They found that Apoe^−/− and APOE4 mice, but not APOE2 or APOE3 mice, had severe BBB defects that were caused by defective regulation of the levels of cyclophilin A (CypA). Increased levels of CypA in Apoe^−/− and APOE4 mice caused activation of NFκB, which in turn increased the expression and activation of MMP-9 in pericytes, which surround the microvasculature. Higher levels of active MMP-9 were shown to compromise BBB integrity in Apoe^−/− and APOE4 mice; notably, effects on the vasculature preceded neurodegeneration. Genetic ablation or pharmacological inhibition of CypA restored the BBB, as did an MMP-9 inhibitor. These results broaden our understanding of how APOE4 might compromise the BBB and thereby contribute to AD and other neuropathologies.