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.