| 摘要 |
Neurovascular disorder critically contributes to the development and pathogenesis of Alzheimer's disease (AD). Transcriptional profiling of human brain endothelial cells (BEC) defines a subset of age-independent genes significantly altered in AD including the homebox gene GAX whose expression controls vascular phenotype and is low in AD. By using viral-mediated GAX gene silencing and transfer, restoring GAX expression in AD BEC is angio-genic, transcriptionally suppresses the AFX1 forkhead transcription factor-mediated apoptosis, and increases the levels of a major amyloid beta-peptide (Abeta) clearance receptor, the low density lipoprotein receptor-related protein 1 (LRP-1) at the blood-brain barrier. In a mouse model of Alzheimer's disease, deletion of the Gax gene results in reductions in brain capillary density and the resting cerebral blood flow, loss of angiogenic brain response to hypoxia, and an impaired Abeta brain efflux caused by reduced LRP-1 levels. The link of GAX gene to AD neurovascular dysfunction provides new mechanistic and therapeutic insights into AD.
|
