APOE4, a form of the human apolipoprotein E gene, is a genetic risk factor for Alzheimer’s disease (AD) and is also associated with other forms of neuropathology. APOE4 is thought to compromise the blood-brain barrier (BBB), but the underlying mechanisms have been unclear. Bell et al. addressed this issue by studying the brain microvasculature in several strains of genetically engineered mice: one lacking the mouse Apoe gene, and others expressing human APOE2, APOE3 or APOE4. They found that Apoe−/− and APOE4 mice, but not APOE2 or APOE3 mice, had severe BBB defects that were caused by defective regulation of the levels of cyclophilin A (CypA). Increased levels of CypA in Apoe−/− and APOE4 mice caused activation of NFκB, which in turn increased the expression and activation of MMP-9 in pericytes, which surround the microvasculature. Higher levels of active MMP-9 were shown to compromise BBB integrity in Apoe−/− and APOE4 mice; notably, effects on the vasculature preceded neurodegeneration. Genetic ablation or pharmacological inhibition of CypA restored the BBB, as did an MMP-9 inhibitor. These results broaden our understanding of how APOE4 might compromise the BBB and thereby contribute to AD and other neuropathologies.
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RESEARCH HIGHLIGHT| 01 July 2012
APOE4 impairs blood-brain barrier via cyclophilin A
Online ISSN: 1754-8411
Print ISSN: 1754-8403
Written by editorial staff. © 2012. Published by The Company of Biologists Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0), which permits unrestricted non-commercial use, distribution and reproduction in any medium provided that the original work is properly cited and all further distributions of the work or adaptation are subject to the same Creative Commons License terms
Dis Model Mech (2012) 5 (4): 415.
APOE4 impairs blood-brain barrier via cyclophilin A. Dis Model Mech 1 July 2012; 5 (4): 415. doi:
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