Amyloid β25-35, an amyloid β1-42 surrogate, and proinflammatory cytokines stimulate VEGF-A secretion by cultured, early passage, normoxic adult human cerebral astrocytes

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DOIResolve DOI: http://doi.org/10.3233/JAD2010100471
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TypeArticle
Journal titleJournal of Alzheimer's Disease
Volume21
Issue3
Pages915926; # of pages: 12
SubjectAlzheimer�s disease; amyloid-β peptides; cerebrovascular angiopathy; HIF1; normal adult human astrocytes; proinflammatory cytokines; VEGFA
AbstractCerebrovascular 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, VEGFA gene upregulation, with increased VEGFA 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] +tumor necrosis factor [TNF]-α), or pair (IFN-y +TNF-α) like those produced in LOAD brains) stimulates the nuclear translocation of stabilized hypoxiainducible factor (HIF)1α protein and its binding to VEGFA hypoxiaresponse elements; the mRNA synthesis for three VEGFA splice variants (121, 165, 189); and the secretion of VEGFA165. The CMtrio was the most powerful stimulus, IFN-y +TNF-α was less potent, and other cytokine pairs or single cytokines or Aβ35−25 were ineffective. While Aβ25−35 did not change HIF1β protein levels, the CMtrio increased both HIF1α and HIF1β protein levels, thereby giving an earlier and stronger stimulus to VEGFA secretion by NAHAs. Thus, increased VEGFA secretion from astrocytes stimulated by Aβ1−42 and by microgliareleased cytokines might restore angiogenesis and Aβ1−42 vascular clearance.
Publication date
LanguageEnglish
AffiliationNRC Institute for Biological Sciences; National Research Council Canada
Peer reviewedYes
NPARC number17480352
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Record identifier7799e758-305b-4ff0-a7b1-99a9a4e14d0f
Record created2011-03-30
Record modified2016-05-09
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