喹啉类分子在AD转基因鼠模型中的神经保护作用及机制研究

Aβ is a initiator of alzheimer's disease and it cause the complex pathology at the early stage of neurodegeneration. As major toxic peptides，Aβ oligomers, contribute to the loss of neuron during the process of AD. Recently, it was found that Aβ oligomers can act as a ligand of PrPc and cause the aggregation of amyloid and tau protein within neuron. Parts of the oligomers can spread among cells in a prion-like manner, which accelerate the neurodegeneration.We found that Aβ oligomers can induce autophagy at the early stage and inhibit autophagy at the later stage which provide the surrounding for toxic prtein aggregation within cells in our previous work. The screen of small molecular anti-prion compounds is mature for the treatment of transmissible spongiform encephalopathies. Among small molecular library with druggability, we found that 2-(2-furyl)quinoline-4-carboxylic acid protected cells against oxidative stress and promoted tissue regeneration. In addition, we found that it also alleivated the aggregation of tau protein within neuronal cells after incubated with Aβ oligomers. Therefore, we hypothesize that quinoline derived compound can competitively repalce amyloid oligoners by binding with PrPc on the surface of neuron at the early stage of AD. It can keep the physiologic function of PrPc and provide neuroprotective effect by maintaining basic autophagy and avoiding the inhibition of autophagy induced by Aβ oligomers. It can also protect against the abnormal protein protein aggregation within cells and the secondary oligomers spreading in a prion-like manner among cells induced by Aβ oligomers. The provement of this hypothesis may provide new targets and solution for AD treatment.

Aβ做为阿尔茨海默病复杂病理变化的早期启动者在AD发生、发展中具有重要作用，Aβ寡聚体是神经细胞损失的主要毒性肽。近来发现：Aβ寡聚体可以通过神经细胞上的PrPc受体造成神经细胞内Aβ和tau蛋白形成聚集，部分寡聚体以prion-样成核传播，加速脑的退行性变，我们前期发现：Aβ寡聚体早期激活诱导性自噬，后期造成自噬抑制，为细胞内毒蛋白聚集创造条件。小分子抗prion化合物在治疗传播性海绵状脑病的筛选成熟，在具备成药性的小分子化合物库筛选中，我们发现2-(2-呋喃)喹啉-4-羧酸具有明显的细胞保护和促进再生作用，减少Aβ寡聚体诱发的tau寡聚体，我们认为：早期给予喹啉类prion拮抗剂可能和Aβ寡聚体竞争PrPc,维持PrPc神经保护的生理功能，维持基础性自噬，避免自噬抑制,对抗Aβ造成的神经细胞内异常蛋白聚集及传播。该学说的证明有利于为AD治疗提治疗供新的靶点和思路。

PrPc是淀粉样蛋白寡聚体神经表面天然受体，近年来受到人们的广泛关注,被认为是阿尔茨海默病的潜在治疗靶点。以往研究主要集中在淀粉样蛋白寡聚体和PrPc结合后引起谷氨酸释放量增加，通过谷氨酸受体造成神经细胞凋亡。我们发现淀粉样蛋白寡聚体可以造成显著提高PrPc mRNA，并使Aβ插入PrPc蛋白结构，形成稳定的病理性二聚体显著增高，AβO和膜表面受体内吞后显著抑制自噬流，促进Beclin1核转位，自噬泡无法与溶酶体结合，细胞内p62蛋白含量显著增高，反馈性抑制细胞内内源性Aβ及APP蛋白表达，tau蛋白细胞内水平显著增高,导致细胞老化。采用喹啉化合物QLCA及PrPc siRNA均可显著减少PrPc二聚体生成，减轻自噬关键蛋白p62及tau蛋白细胞内堆积,减轻神经细胞老化。与对照组相比，AβO可显著降低神经细胞sirt3、PDHE1, PFKB3，增加MCT1、MCT4表达，喹啉化合物QLCA可显著提高神经细胞sirt3, 蛋白表达量，提高糖酵解蛋白PFKB3、PDHE1及PKM2蛋白表达量，减少MCT1、MCT4蛋白量，提示喹啉化合物QLCA提高线粒体抗氧化能力，提高葡萄糖在线粒体三羧酸循环及糖酵解效率。此外，QLCA可显著改善APP-PS1小鼠的认知，减轻焦虑及脑部Aβ沉积。天然化合物穿心莲内酯可以减轻AβO造成的细胞凋亡，提高PrPc生理性N-糖基化二聚体含量, 增强神经细胞对葡萄糖摄取，调节线粒体糖酵解和线粒体动力学，增强细胞自噬能力，抑制细胞老化。

内容获取失败，请点击重试