Relationship Between Cyclophilin A Levels and Matrix Metalloproteinase 9 Activity in Cerebrospinal Fluid of Cognitively Normal Apolipoprotein E4 Carriers and Blood-Brain Barrier Breakdown

In humans, apolipoprotein E (apoE) has 3 isoforms: apoE2, apoE3, and apoE4.APOE4 is a major genetic risk factor for Alzheimer disease (AD). 1 Apolipoprotein E4 has direct effects on the cerebrovascular system, resulting in microvascular lesions and blood-brain barrier (BBB) damage, as recently reviewed. 25][6] Our recent studies in transgenic mice have demonstrated that apoE4 leads to BBB breakdown by activating the proinflammatory cyclophilin A (CypA)-matrix metalloproteinase 9 (MMP-9) pathway in brain pericytes, which in turn results in degradation of the BBB tight junctions and basement membrane proteins. 7It has also been shown that apoE4-mediated BBB breakdown leads to secondary neuronal injury and cognitive decline in transgenic mice. 7Apolipoprotein E2 and apoE3 maintained normal BBB integrity in transgenic mice by suppressing the CypA-MMP-9 pathway. 7Here, we studied the cerebrospinal fluid (CSF)/plasma albumin quotient (Q Alb ), an established marker of BBB breakdown, 8 and CypA and active MMP-9 levels in the CSF of cognitively normal individuals with different APOE genotypes to determine whether apoE4dependent changes in BBB permeability and CypA-MMP-9 pathway as shown in APOE4, but not APOE3 and APOE2 transgenic mice, also occur in humans.