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首页> 外文期刊>Life sciences >Sortilin is required for toxic action of Aβ oligomers (AβOs): Extracellular AβOs trigger apoptosis, and intraneuronal AβOs impair degradation pathways
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Sortilin is required for toxic action of Aβ oligomers (AβOs): Extracellular AβOs trigger apoptosis, and intraneuronal AβOs impair degradation pathways

机译：sortilin是Aβ低​​聚物（AβOs）毒性作用所必需的：细胞外AβOs触发细胞凋亡，神经内AβOs破坏降解途径

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Aims: We investigated the pathological relevance of the Aβ oligomer (AβO) cascade hypothesis in 3xTg-AD mice. This study was also designed to elucidate the molecular mechanism underlying the toxic action of AβOs. Main methods: To target the extracellular AβOs in vivo, a monoclonal antibody specific for AβOs was developed using a novel method. Monoclonal 72D9 was intravenously administered to aged 3xTg-AD mice bearing the human AD pathology to investigate the relevance of the AβO cascade hypothesis. To further identify the AβO-binding molecule on the cell surface, small interfering RNA (siRNA) for sortilin was transfected into SH-SY5Y cells. The sortilin-dependent molecular mechanism underlying toxic action of AβOs and/or AβO endocytosis was also assessed in cultured cortical neurons forming synapses. Key findings: The 72D9 immunotherapy of aged 3xTg-AD mice revealed that extracellular and intraneuronal AβOs are related, and that intraneuronal AβOs act upstream of tau. We also found that extracellular AβOs first act as a sortilin ligand, and then induce p75 NTF-mediated apoptosis, endocytosis-induced attenuation of autophagy, or accumulation of AβOs in autophagosomes. Significance: Taken together, these findings provide novel lines of evidence that sortilin governs the toxic action of extracellular AβOs, which affects the degradation and/or clearance of either intraneuronal AβOs or tau. Thus, therapeutic intervention targeting extracellular AβOs themselves or for preventing the interaction between intraneuronal AβOs and tau is a promising strategy to be developed for AD treatment.
机译：目的：我们研究了3xTg-AD小鼠中Aβ寡聚物（AβO）级联假说的病理相关性。这项研究还旨在阐明AβOs毒性作用的分子机制。主要方法：为了在体内靶向细胞外AβO，使用一种新方法开发了一种对AβOs特异的单克隆抗体。将单克隆72D9静脉注射给患有人AD病理的老年3xTg-AD小鼠，以研究AβO级联假说的相关性。为了进一步鉴定细胞表面的AβO结合分子，将sortilin的小干扰RNA（siRNA）转染到SH-SY5Y细胞中。在形成突触的皮层神经元中，还评估了AβOs和/或AβO内吞作用毒性作用的分选蛋白依赖性分子机制。关键发现：老年3xTg-AD小鼠的72D9免疫疗法揭示了细胞外和神经内AβOs相关，并且神经内AβOs在tau上游起作用。我们还发现，细胞外AβOs首先充当sortilin配体，然后诱导p75 NTF介导的凋亡，内吞作用诱导的自噬减弱或自噬小体中AβOs的积累。启示：综上所述，这些发现提供了新的证据，表明sortilin控制细胞外AβOs的毒性作用，这影响神经内AβOs或tau的降解和/或清除。因此，针对细胞外AβOs本身或防止神经内AβOs与tau之间相互作用的治疗性干预是开发用于AD治疗的有希望的策略。

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