Journal
NATURE MEDICINE
Volume 11, Issue 9, Pages 959-965Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm1287
Keywords
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Funding
- NATIONAL INSTITUTE ON AGING [R43AG024002, R43AG023993, R37AG023084] Funding Source: NIH RePORTER
- NIA NIH HHS [R43 AG24002, R43 AG23993, R37 AG023084] Funding Source: Medline
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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 ( Ab) 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 Ab 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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