Relationship between cyclophilin a levels and matrix metalloproteinase 9 activity in cerebrospinal fluid of cognitively normal apolipoprotein e4 carriers and blood-brain barrier breakdown.

Relationship Between Cyclophilin A Levels and MatrixMetalloproteinase 9Activity 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 amajor genetic risk factor forAlzheimer disease (AD).1 Apolipoprotein E4 has direct effects on the cerebrovascular system, resulting inmicrovascular lesions and blood-brain barrier (BBB) damage, as recently reviewed.2 Neurovascular dysfunction is also present in cognitively normalAPOE4carriersand individualswithAPOE4-associateddisorders includingAD.1-3Moreover,postmortembraintissueanalysishas indicatedthatBBBbreakdowninpatientswithADismore pronounced in APOE4 carriers compared with APOE3 or APOE2.4-6 Our recent studies in transgenic mice have demonstratedthatapoE4leadstoBBBbreakdownbyactivatingtheproinflammatory 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.7 It has also been shown that apoE4-mediated BBBbreakdown leads to secondaryneuronal injury and cognitive decline in transgenic mice.7 Apolipoprotein E2 and apoE3 maintained normal BBB integrity in transgenic mice by suppressing the CypA–MMP-9 pathway.7 Here, we studied the cerebrospinal fluid (CSF)/plasma albumin quotient (QAlb), an established marker of BBB breakdown,8 and CypA and active MMP-9 levels in theCSFof cognitivelynormal individualswith different APOE genotypes to determine whether apoE4dependentchanges inBBBpermeabilityandCypA–MMP-9pathway as shown inAPOE4, but notAPOE3 andAPOE2 transgenic mice, also occur in humans.