Relationship between cyclophilin A levels and matrix metalloproteinase 9 activity in cerebrospinal fluid of cognitively normal apolipoprotein E4 carriers and blood-brain barrier breakdown

摘要

In humans, apolipoprotein E (apoE) has 3 isoforms: apoE2, apoE3, and apoE4. AP0E4 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. Neurovascular dysfunction is also present in cognitively nor-malAP0E4 carriers and individuals with APOE4-associated disorders including AD. Moreover, postmortem brain tissue analysis has indicated that BBB breakdown in patients with AD is more pronounced in APOE4 carriers compared with APOE3 or APOE2. Our recent studies in transgenic mice have demonstrated that apoE4 leads to BBB breakdown by activating the pro-inflammatory 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. It has also been shown that apoE4-mediated BBB breakdown leads to secondary neuronal injury and cognitive decline in transgenic mice. Apolipoprotein E2 and apoE3 maintained normal BBB integrity in transgenic mice by suppressing the CypA-MMP-9 pathway. Here, we studied the ce-rebrospinal fluid (CSF)/plasma albumin quotient (QW, an established marker of BBB breakdown, and CypA and active MMP-9 levels in the CSF of cognitively normal individuals with different APOE genotypes to determine whether apoE4-dependent changes in BBB permeability and CypA-MMP-9 pathway as shown in APOE4, but not APOE3 and AP0E2 transgenic mice, also occur in humans.