Amyloid-β25-35, an Amyloid-β1-42 Surrogate, and Proinflammatory Cytokines Stimulate VEGF-A Secretion by Cultured, Early Passage, Normoxic Adult Human Cerebral Astrocytes

Cerebrovascular angiopathy affects late-onset Alzheimer's disease (LOAD) brains by possibly increasing vascular endothelial growth factor (VEGF). A expression, thereby stimulating endothelial cell proliferation and migration. Indeed, VEGF-A gene upregulation, with increased VEGF-A protein content of reactive astrocytes and microglia, occurs in LOAD brains, and neovascularization was observed one week after injecting amyloid-beta (A beta)(1-42) into rat hippocampus. We have now found, with cultured 'normoxic' normal adult human astrocytes (NAHAs), that fibrillar A beta(25-35) (an active A beta(1-42) fragment) or a cytokine mixture (the (CM)-trio (interleukin [IL]-1 beta+interferon [IFN]-gamma+tumor necrosis factor [TNF]-alpha), or pair (IFN-gamma+TNF-alpha) like those produced in LOAD brains) stimulates the nuclear translocation of stabilized hypoxia-inducible factor (HIF)-1 alpha protein and its binding to VEGF-A hypoxia-response elements; the mRNA synthesis for three VEGF-A splice variants (121, 165, 189); and the secretion of VEGF-A(165). The CM-trio was the most powerful stimulus, IFN-gamma+TNF-alpha was less potent, and other cytokine pairs or single cytokines or A beta(35-25) were ineffective. While A beta(25-35) did not change HIF-1 beta protein levels, the CM-trio increased both HIF-1 alpha and HIF-1 beta protein levels, thereby giving an earlier and stronger stimulus to VEGF-A secretion by NAHAs. Thus, increased VEGF-A secretion from astrocytes stimulated by A beta(1-42) and by microglia-released cytokines might restore angiogenesis and A beta(1-42) vascular clearance.