Role of the MEOX2 homeobox gene in neurovascular dysfunction in Alzheimer disease.
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.
Wu
Zhenhua
Z
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.
Guo
Huang
H
Chow
Nienwen
N
Sallstrom
Jan
J
Bell
Robert D
RD
Deane
Rashid
R
Brooks
Andrew I
AI
Kanagala
Suhasini
S
Rubio
Anna
A
Sagare
Abhay
A
Liu
Dong
D
Li
Fang
F
Armstrong
Don
D
Gasiewicz
Thomas
T
Zidovetzki
Raphael
R
Song
Xiaomei
X
Hofman
Florence
F
Zlokovic
Berislav V
BV
D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology*; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000098:blood supply*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D005625:Frontal Lobe / Q000098:blood supply; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D005801:Genes, Homeobox; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000235:genetics
D018398:Homeodomain Proteins; C484193:MEOX2 protein, human; C484194:Meox2 protein, mouse