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Article
Nature Medicine 11, 959 - 965 (2005)
Published online: 14 August 2005; | doi:10.1038/nm1287

Role of the MEOX2 homeobox gene in neurovascular dysfunction in Alzheimer disease

Zhenhua Wu1, 7, Huang Guo1, 2, 7, Nienwen Chow2, 7, Jan Sallstrom2, 7, Robert D Bell2, Rashid Deane1, Andrew I Brooks3, Suhasini Kanagala2, Anna Rubio2, Abhay Sagare1, Dong Liu1, Fang Li2, Don Armstrong2, 4, Thomas Gasiewicz5, Raphael Zidovetzki2, 4, Xiaomei Song1, Florence Hofman2, 6 & Berislav V Zlokovic1, 2

1  Frank P. Smith Laboratories for Neuroscience and Neurosurgical Research, University of Rochester Medical Center, Arthur Kornberg Medical Research Building, 601 Elmwood Avenue, Box 670, Rochester, New York 14642, USA.

2  Socratech Research Laboratories, 625 Elmwood Avenue, Rochester, New York 14620, USA.

3  Genomics Center, University of Rochester Medical Center, 575 Elmwood Avenue, Box EHSC, Rochester, New York 14642, USA.

4  Department of Cell Biology and Neuroscience, University of California Riverside, 1208 Spieth Hall, Riverside, California 92521, USA.

5  Department of Environmental Medicine, University of Rochester School of Medicine & Dentistry, Box EHSC, 575 Elmwood Avenue, Rochester, New York 14642, USA.

6  Department of Pathology, Keck School of Medicine, University of Southern California, Hoffman Medical Research Center 209, 2011 Zonal Avenue, Los Angeles, California 90089-9092, USA.

7  These authors contributed equally to this work.

Correspondence should be addressed to Berislav V Zlokovic berislav_zlokovic@urmc.rochester.edu

Neurovascular dysfunction substantially contributes to Alzheimer disease. Here, we show that transcriptional profiling of human brain endothelial cells (BECs) defines a subset of genes whose expression is age-independent but is considerably altered in Alzheimer disease, including the homeobox gene MEOX2 (also known as GAX), a regulator of vascular differentiation, whose expression is low in Alzheimer disease. By using viral-mediated MEOX2 gene silencing and transfer, we show that restoring expression of the protein it encodes, GAX, in BECs from individuals with Alzheimer disease stimulates angiogenesis, transcriptionally suppresses 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), at the blood-brain barrier. In mice, deletion of Meox2 (also known as Gax) results in reductions in brain capillary density and resting cerebral blood flow, loss of the angiogenic response to hypoxia in the brain and an impaired Abeta efflux from brain caused by reduced LRP levels. The link of MEOX2 to neurovascular dysfunction in Alzheimer disease provides new mechanistic and therapeutic insights into this illness.

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ISSN: 1078-8956
EISSN: 1546-170X
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