Credit: Image courtesy of D. Jones.

Despite many recent advances, the pathogenesis of Alzheimer's disease is still unclear. Wu and colleagues bring us another step closer to understanding this process by describing how the gene MEOX2 (mesenchyme homeobox 2, also known as GAX) contributes to neuronal and vascular dysfunction in this disorder.

The authors compared profiles of mRNA expression in diseased human brain endothelial cells with control samples to identify targets in Alzheimer's disease. This revealed that the expression of a small subset of genes, which includes the homeobox gene MEOX2, is altered in the disease — specifically, MEOX2 is expressed at a lower level in cells affected by Alzheimer's disease than in healthy cells. Because homeobox genes have key roles in vascular differentiation, the authors speculated that restoring GAX expression could correct the abnormalities in the neurovasculature in Alzheimer's disease.

By first silencing and then restoring MEOX2 expression, the authors showed that MEOX2 plays an important part in two important processes. As well as stimulating the formation of new blood vessels (angiogenesis), a process that is impaired in Alzheimer's disease, restoration of GAX expression also increased the suppression of a transcription factor — the AFX-1 forkhead transcription factor — that is involved in apoptosis.

Following on from these findings, Wu and colleagues investigated the role of MEOX2 in the clearance of the abnormal amyloid-β protein. Mice with only one copy of Meox2 showed decreased expression of lipoprotein receptor-related protein 1 (LRP), which is a clearance receptor that is involved in the efflux of amyloid-β. However, the reduction in LRP expression was reversed on transduction of Meox2 into diseased brain endothelial cells.

At present, there is no cure for Alzheimer's disease. The establishment of a link between the decreased expression of MEOX2 and the impaired neurovascular functions that are thought to be involved in the pathology of this debilitating disease make this homeobox gene an attractive target for the treatment of Alzheimer's disease.