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Research Letter |

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

Matthew R. Halliday, BS1,2; Nunzio Pomara, MD3; Abhay P. Sagare, PhD2; Wendy J. Mack, PhD4; Blas Frangione, MD, PhD3; Berislav V. Zlokovic, MD, PhD2
[+] Author Affiliations
1Neuroscience Graduate Program, University of Southern California, Los Angeles
2Department of Physiology and Biophysics, Center for Neurodegeneration and Regeneration, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles
3Department of Psychiatry, Nathan S. Kline Institute for Psychiatric Research, New York University School of Medicine, Orangeburg
4Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles
JAMA Neurol. 2013;70(9):1198-1200. doi:10.1001/jamaneurol.2013.3841.
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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.2 Neurovascular dysfunction is also present in cognitively normal APOE4 carriers and individuals with APOE4-associated disorders including AD.13 Moreover, postmortem brain tissue analysis has indicated that BBB breakdown in patients with AD is more pronounced in APOE4 carriers compared with APOE3 or APOE2.46 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.7 It has also been shown that apoE4-mediated BBB breakdown leads to secondary neuronal 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 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 APOE2 transgenic mice, also occur in humans.

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Figure.
Age-Dependent Blood-Brain Barrier Breakdown and Elevated Cyclophilin A and Active Matrix Metalloproteinase 9 (MMP-9) Levels in Cerebrospinal Fluid (CSF) of Cognitively Normal Apolipoprotein E4 (APOE4) Carriers

Cerebrospinal fluid/plasma albumin quotient (A), CSF levels of cyclophilin A (B), and CSF levels of active MMP-9 (C) in a population of cognitively normal individuals on 3 different APOE genotypes: APOE2/E3 (n = 11), APOE3/E3 (n = 28), and APOE3/E4 (n = 10). Pearson correlation coefficients (r) were calculated to study the relationship between CSF cyclophilin A (D) and CSF active MMP-9 (E) levels with albumin quotient in individual subjects. D and E, Points represent individual values from 49 subjects. The black bars represent mean values. aP < .01 and bP < .05.

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