Valerio Alessandra, Boroni Flora, Benarese Marina, Sarnico Ilenia, Ghisi Valentina, Bresciani Laura Grazia, Ferrario Marina, Borsani Giuseppe, Spano PierFranco, Pizzi Marina
Division of Pharmacology, Department of Biomedical Sciences & Biotechnologies, University of Brescia, Italy.
Eur J Neurosci. 2006 Apr;23(7):1711-20. doi: 10.1111/j.1460-9568.2006.04722.x.
Beta-amyloid (Abeta) peptides are key proteins in the pathophysiology of Alzheimer's disease (AD). While Abeta42 aggregates very rapidly to form early diffuse plaques, supplemental Abeta40 deposition is required to form mature neuritic plaques. We here investigated the role of nuclear factor-kappaB (NF-kappaB) pathway in Abeta40-mediated neuronal damage and amyloid pathology. In rat primary neurons and human postmitotic neuronal cells, the Abeta peptide induced a dose-dependent neuronal death, reduced the levels of the anti-apoptotic protein Bcl-XL, enhanced the cytosolic release of cytochrome c, and elicited the intracellular accumulation and secretion of Abeta42 oligomers. Moreover, Abeta40 activated the NF-kappaB pathway by selectively inducing the nuclear translocation of p65 and p50 subunits, and promoted an apoptotic profile of gene expression. As inhibitors of the NF-kappaB pathway, we tested the capability of a double-stranded kappaB decoy oligonucleotide, the anti-inflammatory drug aspirin and the selective IkappaB kinase 2 inhibitor, AS602868, to modify the Abeta40-mediated effects. These treatments, transiently applied before Abeta exposure, completely inhibited p50/p65 nuclear translocation and neuronal damage. The kappaB decoy also inhibited the Abeta-induced release of cytochrome c, restored the levels of Bcl-XL, and prevented intraneuronal accumulation and secretion of Abeta42. These results open up interesting perspectives on the development of novel strategies targeting out NF-kappaB p50/p65 dimers for pharmacological intervention in AD.
β-淀粉样蛋白（Aβ）肽是阿尔茨海默病（AD）病理生理学中的关键蛋白。虽然Aβ42能非常迅速地聚集形成早期弥漫性斑块，但形成成熟的神经炎性斑块还需要额外的Aβ40沉积。我们在此研究了核因子-κB（NF-κB）通路在Aβ40介导的神经元损伤和淀粉样病理中的作用。在大鼠原代神经元和人有丝分裂后神经元细胞中，Aβ肽诱导剂量依赖性的神经元死亡，降低抗凋亡蛋白Bcl-XL的水平，增强细胞色素c的胞质释放，并引发Aβ42寡聚体的细胞内积累和分泌。此外，Aβ40通过选择性诱导p65和p50亚基的核转位激活NF-κB通路，并促进基因表达的凋亡特征。作为NF-κB通路的抑制剂，我们测试了双链κB诱饵寡核苷酸、抗炎药物阿司匹林和选择性IκB激酶2抑制剂AS602868改变Aβ40介导效应的能力。在Aβ暴露前短暂应用这些处理，可完全抑制p50/p65核转位和神经元损伤。κB诱饵还抑制了Aβ诱导的细胞色素c释放，恢复了Bcl-XL的水平，并阻止了Aβ42在神经元内的积累和分泌。这些结果为开发针对NF-κB p50/p65二聚体的新型策略用于AD的药物干预开辟了有趣的前景。
