Targeting Hsc70-based autophagy to eliminate amyloid β oligomers
Targeting Hsc70-based autophagy to eliminate amyloid β oligomers
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DOI：
10.1016/j.bbrc.2020.02.016
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发表时间：
2020-04-16
影响因子：
3.1
通讯作者：
Li, Wenming
中科院分区：
文献类型：
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作者：
Dou, Juan;Su, Peng;Li, Wenming
β淀粉样蛋白（A β）寡聚体可能是阿尔茨海默病（AD）发病机制中的真实的罪魁祸首;因此，消除这些毒性寡聚体对于AD治疗可能具有重要意义。自噬是溶酶体降解胞质组分的分解代谢过程，热休克同源70 kDa蛋白（Hsc 70）与具有其KFERQ样基序[也称为分子伴侣介导的自噬（CMA）基序]的蛋白质结合，并通过CMA将其携带到溶酶体或通过内体微自噬（eMI）将其携带到晚期内体进行降解。在这项研究中，我们的策略是使病理性抗体成为一个选择性和合适的底物CMA和eMI（称为Hsc 70为基础的自噬），通过标记其寡聚体与多个CMA模体。首先，我们设计并合成了具有三个CMA基序的A β寡聚体结合肽。其次，我们确定肽可以帮助A β寡聚体进入内体和溶酶体，这可以通过酮进一步增强。更重要的是，我们发现该肽可以显著减少来自AD患者成纤维细胞的诱导多能干细胞（iPSC）皮质神经元中的A β寡聚体，并保护原代培养的皮质神经元免受Ab寡聚体诱导的神经毒性。总之，我们证明了靶向Hsc 70的自噬肽可以有效地消除Ab寡聚体，并具有上级神经保护活性。(C)2020爱思唯尔公司All rights reserved.
Amyloid beta (A beta) oligomers may be a real culprit in the pathogenesis of Alzheimer's disease (AD); therefore, the elimination of these toxic oligomers may be of great significance for AD therapy. Autophagy is the catabolic process by which lysosomes degrade cytosolic components, and heat shock cognate 70 kDa protein (Hsc70) binds to proteins with their KFERQ-like motifs [also known as chaperone-mediated autophagy (CMA) motifs] and carries them to lysosomes through CMA or late endosomes through endosomal microautophagy (eMI) for degradation. In this study, our strategy is to make the pathological Ab become one selective and suitable substrate for CMA and eMI (termed as Hsc70-based autophagy) by tagging its oligomers with multiple CMA motifs. First, we design and synthesize A beta oligomer binding peptides with three CMA motifs. Second, we determine that the peptide can help A beta oligomers enter endosomes and lysosomes, which can be further enhanced by ketone. More importantly, we find that the peptide can dramatically reduce A beta oligomers in induced pluripotent stem cell (iPSC) cortical neurons derived from AD patient fibroblasts and protect primary cultured cortical neurons against the Ab oligomer-induced neurotoxicity. In conclusion, we demonstrate that the peptide targeting Hsc70-based autophagy can effectively eliminate Ab oligomers and have superior neuroprotective activity. (C) 2020 Elsevier Inc. All rights reserved.