Amyloid-β(25-35), an amyloid-β(1-42) 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-β (Aβ)(1-42) into rat hippocampus. We have now found, with cultured 'normoxic' normal adult human astrocytes (NAHAs), that fibrillar Aβ(25-35) (an active Aβ(1-42) fragment) or a cytokine mixture (the (CM)-trio (interleukin [IL]-1β+interferon [IFN]-γ+tumor necrosis factor [TNF]-α), or pair (IFN-γ+TNF-α) like those produced in LOAD brains) stimulates the nuclear translocation of stabilized hypoxia-inducible factor (HIF)-1α 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-A165. The CM-trio was the most powerful stimulus, IFN-γ+TNF-α was less potent, and other cytokine pairs or single cytokines or Aβ(35-25) were ineffective. While Aβ(25-35) did not change HIF-1β protein levels, the CM-trio increased both HIF-1α and HIF-1β protein levels, thereby giving an earlier and stronger stimulus to VEGF-A secretion by NAHAs. Thus, increased VEGF-A secretion from astrocytes stimulated by Aβ(1-42) and by microglia-released cytokines might restore angiogenesis and Aβ(1-42) vascular clearance.
Chiarini
Anna
A
Department of Life and Reproduction Sciences, University of Verona Medical School, Verona, Italy.
Whitfield
James
J
Bonafini
Clara
C
Chakravarthy
Balu
B
Armato
Ubaldo
U
Dal Prà
Ilaria
I
D000293:Adolescent; D000328:Adult; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016207:Cytokines; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010446:Peptide Fragments; D020033:Protein Isoforms; D042461:Vascular Endothelial Growth Factor A; C074636:amyloid beta-protein (25-35)