Histology and Embryology Section, Department of Life and Reproduction Sciences, University of Verona Medical School, Verona, Italy.
J Alzheimers Dis. 2011;24(2):335-47. doi: 10.3233/JAD-2011-101626.
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.
在患有阿尔茨海默病（AD）的淀粉样蛋白β（Aβ）₄₂ 蓄积的人类大脑中的星形胶质细胞中，血管内皮生长因子（VEGF）-A 的合成上调，并且也充满了 Aβ₄₂。我们已经表明，Aβ（25-35）（Aβ₄₂ 的替代物）在早期传代正常人类星形胶质细胞（NAHAs）的“常氧”培养物中诱导的 VEGF-A 产生是由 VEGF 基因刺激的缺氧诱导因子（HIF）-1α的稳定化介导的 -1α 和 HIF-1α•HIF-1β 复合物的核转位。我们现在发现，用 Aβ（25-35）处理这些 NAHAs 也会刺激它们产生 Aβ₄₂（在免疫印迹中出现几种分子量为 8 kDa 以上的条带），其水平在 48 小时达到峰值（与 0 小时相比为 2.8 倍，p <0.001），然后开始缓慢下降。这种 Aβ₄₂ 肽产生的增加与 HIF-1α 的短暂增加相吻合（因此 HIF-1α•HIF-1β 复合物；在 24 小时时，与 0 小时相比为 1.5 倍，p <0.001）进入细胞核，首先是 β-分泌酶（BACE-1/β-S）mRNA 表达的短暂激增（与 0 小时相比为 1.2 倍，p = 0.013）和活性峰值在 24 小时（与 0 小时相比为 1.4 倍，p = 0.001），然后是 γ-分泌酶（γ-S）活性在 48 小时达到峰值（与 0 小时相比为 1.6 倍，p <0.001），从淀粉样蛋白-β 蛋白前体中切割出 Aβ₄₂ 肽。由于这两种分泌酶的基因编码成分在其启动子中具有与 VEGF 基因相同的 HIF-1α•HIF-1β 反应元件，因此这些观察结果表明，AD 大脑中神经元释放的 Aβ₄₂ 可以通过 HIF-1α•HIF-1β 信号转导将相关星形胶质细胞募集到产生 Aβ₄₂ 的细胞池中。换句话说，Aβ₄₂ 在 NAHAs 中产生 Aβ₄₂。
