Deficiency of Brain ATP-Binding Cassette Transporter A-1 Exacerbates Blood–Brain Barrier and White Matter Damage After Stroke
Background and Purpose—The ATP-binding cassette transporter A-1 (ABCA1) gene is a key target of the transcription factors liver X receptors. Liver X receptor activation has anti-inflammatory and neuroprotective effects in animal ischemic stroke models. Here, we tested the hypothesis that brain ABCA1 reduces blood–brain barrier (BBB) and white matter (WM) impairment in the ischemic brain after stroke.
Methods—Adult brain-specific ABCA1–deficient (ABCA1−B/−B) and floxed-control (ABCA1fl/fl) mice were subjected to permanent distal middle cerebral artery occlusion and were euthanized 7 days after distal middle cerebral artery occlusion. Functional outcome, infarct volume, BBB leakage, and WM damage were analyzed.
Results—Compared with ABCA1fl/fl mice, ABCA1−B/−B mice showed marginally (P=0.052) increased lesion volume but significantly increased BBB leakage and WM damage in the ischemic brain and more severe neurological deficits. Brain ABCA1–deficient mice exhibited increased the level of matrix metalloproteinase-9 and reduced the level of insulin-like growth factor 1 in the ischemic brain. BBB leakage was inversely correlated (r=−0.073; P<0.05) with aquaporin-4 expression. Reduction of insulin-like growth factor 1 and aquaporin-4, but upregulation of matrix metalloproteinase-9 expression were also found in the primary astrocyte cultures derived from ABCA1−B/−B mice. Cultured primary cortical neurons derived from C57BL/6 wild-type mice with ABCA1−B/−B astrocyte–conditioned medium exhibited decreased neurite outgrowth compared with culture with ABCA1fl/fl astrocyte–conditioned medium. ABCA1−B/−B primary cortical neurons show significantly decreased neurite outgrowth, which was attenuated by insulin-like growth factor 1 treatment.
Conclusions—We demonstrate that brain ABCA1 deficiency increases BBB leakage, WM/axonal damage, and functional deficits after stroke. Concomitant reduction of insulin-like growth factor 1 and upregulation of matrix metalloproteinase-9 may contribute to brain ABCA1 deficiency–induced BBB and WM/axonal damage in the ischemic brain.
- aquaporin 4
- ATP binding cassette transporter A-1
- blood–brain barrier
- insulin-like growth factor binding protein 1
- white matter
- Received August 18, 2014.
- Revision received December 16, 2014.
- Accepted December 19, 2014.
- © 2015 American Heart Association, Inc.