Apolipoprotein E controls cerebrovascular integrity via cyclophilin A

The APOE4-mediated proinflammatory pathway is shown to initiate blood–brain barrier breakdown and resulting neurodegeneration in transgenic mice. Restoring the blood–brain barrier There are known connections between the Alzheimer's-disease-linked APOE4 gene and cerebrovascular integrity. However, the mechanisms that drive known blood–brain-barrier dysfunction both in rodent models and in APOE4-associated neurological disorders are unknown. Here, Berislav Zlokovic and colleagues report that APOE4 activates a matrix metalloproteinase pathway in cells forming the blood–brain barrier in mice, leading to its breakdown and the neuronal uptake of blood-derived neurotoxic proteins. In turn, microvascular and cerebral blood flow are reduced; together, these deficits can initiate neurodegenerative changes in rodents. The authors suggest that cyclophilin A (CypA), a component of the APOE4-activated pathway, is a potential target for treating APOE4-mediated neuronal dysfunction. Treatment with the CypA inhibitor cyclosporine A restores the blood–brain barrier in APOE4 mice. Human apolipoprotein E has three isoforms: APOE2, APOE3 and APOE4 1 . APOE4 is a major genetic risk factor for Alzheimer’s disease 2 , 3 and is associated with Down’s syndrome dementia and poor neurological outcome after traumatic brain injury and haemorrhage 3 . Neurovascular dysfunction is present in normal APOE4 carriers 4 , 5 , 6 and individuals with APOE4 -associated disorders 3 , 7 , 8 , 9 , 10 . In mice, lack of Apoe leads to blood–brain barrier (BBB) breakdown 11 , 12 , whereas APOE4 increases BBB susceptibility to injury 13 . How APOE genotype affects brain microcirculation remains elusive. Using different APOE transgenic mice, including mice with ablation and/or inhibition of cyclophilin A (CypA), here we show that expression of APOE4 and lack of murine Apoe, but not APOE2 and APOE3, leads to BBB breakdown by activating a proinflammatory CypA–nuclear factor-κB–matrix-metalloproteinase-9 pathway in pericytes. This, in turn, leads to neuronal uptake of multiple blood-derived neurotoxic proteins, and microvascular and cerebral blood flow reductions. We show that the vascular defects in Apoe- deficient and APOE4 -expressing mice precede neuronal dysfunction and can initiate neurodegenerative changes. Astrocyte-secreted APOE3, but not APOE4, suppressed the CypA–nuclear factor-κB–matrix-metalloproteinase-9 pathway in pericytes through a lipoprotein receptor. Our data suggest that CypA is a key