Rizwan Kalani, MD

Cui X, Chopp M, Zacharek A, Karasinska JM, Cui Y, Ning R, et al. Deficiency of Brain ATP-Binding Cassette Transporter A-1 ExacerbatesBlood–Brain Barrier and White Matter Damage After Stroke. Stroke. 2015

Understanding the normal function of a gene can be assessed in preclinical models by creating a knockout. This allows for evaluation of the pathological state resulting from its absence. The ATP-binding cassette transporter A1 (ABCA1) gene functions in cellular cholesterol efflux for the neurovascular unit and has anti-inflammatory effects. Various proteins affect ACBA1 expression and several others are influenced by its function. Liver X receptors (LXRs) are transcriptional factors that regulate ABCA1 gene expression, whose activation decreases neuroinflammation, promotes synaptic plasticity and axonal regeneration, and improves neurological outcome after ischemic injury. Insulin-like growth factor 1 (IGF1) is involved in neurogenesis and myelination; it decreases cholesterol efflux through ABCA1. It also has neuroprotective properties and reduces stroke-induced blood-brain barrier (BBB) damage. Matrix metalloproteinase 9 (MMP9), with breakdown of its substrates (BBB-tight junction and basement membrane extracellular matrix proteins), contributes to BBB leakage after stroke. Aquaporin-4 in the brain mediates water homeostasis and plays a role in cerebral edema formation.

In this study, Cui et al evaluated the ramifications of ABCA1 deficiency on the BBB, white matter and axonal damage, as well as functional outcome in a murine model of stroke. They took ABCA1 knockout and control mice, subjected them to distal MCA occlusion (dMCAo), and sacrificed them 7 days later. A somatosensory functional test was performed prior to dMCAo and 1, 3, and 7 days afterwards. Histological and immunohistochemical assessment of axons, myelin, and oligodendroglia as well as lesion volume measurement was completed on serial brain sections.

ABCA1 deficiency was associated with a significant increase in neurological deficits at 1, 3, and 7 days after dMCAo as well as increased axonal and white-matter damage in the ischemic region. The authors found increased BBB dysfunction 7 days after dMCAo, evidenced by increased albumin density and decreased aquaporin-4 (AQP4) protein expression, in the ABCA1 deficient mice compared to controls. Increased MMP9 and decreased IGF1 expression was also found in ABCA1 deficient mice. In primary cultured astrocytes that did not express ABCA1, the transcription and translation of MMP9 was increased whereas AQP4 and IGF1 were decreased. Furthermore, neural projection growth was decreased in cultured neurons that did not express brain ABCA1; IGF1 treatment attenuated this reduction.

This study is the first to demonstrate that ABCA1 deficiency increases BBB leakage, tissue injury, and functional deficit after stroke. Alterations in AQP4, MMP9, IGF1, and LXRs after stroke (especially malignant infarction) in human brain needs to be further investigated. Insight gained from this could help better elucidate the pathophysiology of acute tissue injury and cerebral edema after infarction and may lead to novel preventive and therapeutic measures.