The Amyloid-42 Proxy, Amyloid-25-35 , Induces Normal Human Cerebral Astrocytes to Produce Amyloid-42 (original) (raw)
Astrocytes in amyloid-(A) 42-accumulating human brains afflicted with Alzheimer's disease (AD) upregulate vascular endothelial growth factor (VEGF)-A synthesis and also become loaded with A 42. We have already shown that A 25-35 (surrogate of A 42)-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)-1 and nuclear translocation of HIF-1 • HIF-1 complexes. We have now found that treating these NAHAs with A 25-35 also stimulates them to make A 42 (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 A 42 peptide production coincides with a transiently increased flow of HIF-1 (therefore HIF-1 • HIF-1 complexes; at 24 h, 1.5-fold versus 0 h, p < 0.001) into the nucleus and transient surges first of-secretase (BACE-1/-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-secretase (-S) activity cresting at 48 h (1.6-fold versus 0 h, p < 0.001) that cleave the A 42 peptides from amyloid-protein precursor. Since the genes encoding components of these two secretases have the same HIF-1 • HIF-1-responsive elements in their promoters as the VEGF gene, these observations suggest that the A 42 released from neurons in the AD brain can recruit associated astrocytes via HIF-1 • HIF-1 signaling into the pool of A 42-producing cells. In other words, A 42 begets A 42 in NAHAs.
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