title: Brain microvasculature and hypoxia-related proteins in Alzheimer's disease.
abstract: Alzheimer's disease (AD) is a progressive, neurodegenerative disease of increasing incidence. The pathologic processes that underlie this disorder are incompletely understood, however, hypoperfusion/hypoxia is thought to contribute to disease pathogenesis. Hypoxia inducible factor 1-alpha (HIF-1α), a key regulator of cellular responses to hypoxia, is elevated in the microcirculation of AD patients. Cerebral hypoxia is a potent stimulus for vascular activation and angiogenesis. Microvessels isolated from the brains of AD patients express a large number of angiogenic proteins. Despite considerable data in human tissues regarding vascular expression of hypoxia-related angiogenic proteins, there is little information regarding these proteins in the brain vasculature of transgenic AD mice. The objectives of this study were to determine expression of HIF-1α, angiogenic proteins, angiopoietin-2 (Ang-2), and matrix metalloproteinase 2 (MMP2), and survival/apoptotic proteins (Bcl-xL, caspase 3) in the cerebromicrovasculature of AD transgenic mice and to determine the direct effect of hypoxia on cerebral endothelial expression of these proteins in vitro. Cultured brain endothelial cells were subjected to hypoxia for 4-6 h and analyzed by western blot and immunofluorescence. Our results demonstrated that HIF-1α is induced in cultured brain endothelial cells exposed to hypoxia and that expression of Ang-2, MMP2 and caspase 3 was elevated and the anti-apoptotic protein Bcl-xL decreased. Brain sections from AD and control mice showed that HIF-1α, Ang-2, MMP2 and caspase 3 are elevated and Bcl-xL decreased in the microvasculature of AD mice. These data suggest the cerebromicrovasculature is an important target for the effects of hypoxia in the AD brain.
authors: Garrison Institute on Aging and Department of Neurology, Texas Tech University Health Sciences Center Lubbock, TX 79430, USA. paula.grammas@ttuhsc.edu
authors: Paula
authors: P
authors: Grammas
authors: Debjani
authors: D
authors: Tripathy
authors: Alma
authors: A
authors: Sanchez
authors: Xiangling
authors: X
authors: Yin
authors: Jinhua
authors: J
authors: Luo
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000098:blood supply*; D053148:Caspase 3 / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008833:Microcirculation; D051381:Rats; D015854:Up-Regulation; D051020:bcl-X Protein / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D042702:Angiopoietin-2; C494812:Bcl2l1 protein, mouse; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051020:bcl-X Protein; D014841:von Willebrand Factor; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020778:Matrix Metalloproteinase 2