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

Article type: Research Article

Authors: Chiarini, Anna^a | Whitfield, James^b | Bonafini, Clara^a | Chakravarthy, Balu^b | Armato, Ubaldo^{a; *} | Dal Prà, Ilaria^a

Affiliations: [a] Histology and Embryology Unit, Department of Life and Reproduction Sciences, University of Verona Medical School, Verona, Italy | [b] Molecular Signalling Group, National Research Council of Canada, Institute for Biological Sciences, Ottawa, ON, Canada

Correspondence: [*] Correspondence to: Prof. Dr. Ubaldo Armato, MD, Head, Histology & Embryology Unit, Department of Life & Reproduction Sciences, 8 Strada Le Grazie, I-37134 Verona, Italy. Tel./Fax: +39 045 8027159; E-mail: ubaldo.armato@univr.it.

Abstract: 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 Aβ25–35 (an active Aβ1–42 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 Aβ35–25 were ineffective. While Aβ25–35 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 Aβ1–42 and by microglia-released cytokines might restore angiogenesis and Aβ1–42 vascular clearance.

Keywords: Alzheimer's disease, amyloid-β peptides, cerebrovascular angiopathy, HIF-1, normal adult human astrocytes, proinflammatory cytokines, VEGF-A

DOI: 10.3233/JAD-2010-100471

Journal: Journal of Alzheimer's Disease, vol. 21, no. 3, pp. 915-926, 2010