The amyloid-β₄₂ proxy, amyloid-β(25-35), induces normal human cerebral astrocytes to produce amyloid-β₄₂.
Astrocytes in amyloid-β (Aβ)₄₂-accumulating human brains afflicted with Alzheimer's disease (AD) upregulate vascular endothelial growth factor (VEGF)-A synthesis and also become loaded with Aβ₄₂. We have already shown that Aβ(25-35) (surrogate of Aβ₄₂)-induced VEGF-A production in 'normoxic' cultures of early passage normal human cerebral astrocytes (NAHAs) is mediated by the stabilization of VEGF gene-stimulating hypoxia-inducible factor (HIF)-1α and nuclear translocation of HIF-1α•HIF-1β complexes. We have now found that treating these NAHAs with Aβ(25-35) also stimulates them to make Aβ₄₂ (appearing in immunoblots as several bands with M(r)'s from 8 kDa upwards), whose levels peak at 48 h (2.8-fold versus 0 h, p < 0.001) and then start falling slowly. This rise of Aβ₄₂ peptide production coincides with a transiently increased flow of HIF-1α (therefore HIF-1α•HIF-1β complexes; at 24 h, 1.5-fold versus 0 h, p < 0.001) into the nucleus and transient surges first of β-secretase (BACE-1/β-S) mRNA expression (1.2-fold versus 0 h, p = 0.013) and activity peaking at 24-h (1.4-fold versus 0 h, p = 0.001), and then of γ-secretase (γ-S) activity cresting at 48 h (1.6-fold versus 0 h, p < 0.001) that cleave the Aβ₄₂ peptides from amyloid-β protein precursor. Since the genes encoding components of these two secretases have the same HIF-1α•HIF-1β-responsive elements in their promoters as the VEGF gene, these observations suggest that the Aβ₄₂ released from neurons in the AD brain can recruit associated astrocytes via HIF-1α•HIF-1β signaling into the pool of Aβ₄₂-producing cells. In other words, Aβ₄₂ begets Aβ₄₂ in NAHAs.
Histology and Embryology Section, Department of Life and Reproduction Sciences, University of Verona Medical School, Verona, Italy.
Ilaria
I
Dal Prà
James F
JF
Whitfileld
Raffaella
R
Pacchiana
Clara
C
Bonafini
Andrea
A
Talacchi
Balu
B
Chakravarthy
Ubaldo
U
Armato
Anna
A
Chiarini
D000293:Adolescent; D000328:Adult; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D000704:Analysis of Variance; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D001253:Astrocytes / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D055815:Young Adult
D016229:Amyloid beta-Peptides; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010446:Peptide Fragments; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human