Affiliations: [a] Histology and Embryology Section, Department of Life and Reproduction Sciences, University of Verona Medical School, Verona, Italy | [b] Molecular Signaling Group, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Ontario, Canada | [c] Neurosurgery Section, Department of Neurological, Neuropsychological, Morphological and Movement Sciences, University of Verona Medical School, Verona, Italy
Correspondence:
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Correspondence to: Prof. Dr. Ubaldo Armato, MD, Head, Histology and Embryology Section, Department of Life and Reproduction Sciences, 8 Strada Le Grazie, I-37134 Verona, Italy. Tel.:/Fax: +39 045 8027159; E-mail: [email protected].
Abstract: 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 Aβ25-35 (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 Aβ25-35 also stimulates them to make Aβ42 (appearing in immunoblots as several bands with Mr'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.
Keywords: Alzheimer's disease, amyloid-β peptides, β-secretase/BACE-1, γ-secretase, HIF, normal adult human astrocytes
