AP2S1 通过细胞和 APP/PS1 小鼠的晚期内体-溶酶体融合调节 APP 降解,Traffic

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AP2S1 通过细胞和 APP/PS1 小鼠的晚期内体-溶酶体融合调节 APP 降解
Traffic ( IF 3.6 ) Pub Date : 2022-11-22 , DOI: 10.1111/tra.12874
Qi-Xin Wen ₁ , Biao Luo ₁ , Xiao-Yong Xie ₁ , Gui-Feng Zhou ₁ , Jian Chen ₁ , Li Song ₁ , Yue Liu ₁ , Shi-Qi Xie ₁ , Long Chen ₁ , Kun-Yi Li ₁ , Xiao-Jiao Xiang ₂ , Guo-Jun Chen _{1,

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Affiliation

AP2S1 是内吞作用所必需的衔接蛋白 2 (AP2) 的 sigma 2 亚基。在这项研究中，我们研究了 AP2S1 在淀粉样蛋白前体蛋白 (APP) 细胞内加工中的潜在作用，APP 通过产生有毒的 β-淀粉样蛋白肽 (Aβ) 促进阿尔茨海默病 (AD) 的发病机制。我们发现 AP2S1 的敲低或过表达分别降低或增加了稳定表达人全长 APP695 的细胞中 APP 和 Aβ 的蛋白质水平。这种效应与内吞作用无关，但涉及溶酶体降解。形态学研究表明，AP2S1 的沉默促进了 APP 从 RAB9 阳性晚期内体 (LE) 转移到 LAMP1 阳性溶酶体，这与增强的 LE-溶酶体融合平行。在支持下，与 LE-溶血融合有关的液泡蛋白分选相关蛋白 41 (VPS41) 的沉默阻止了 AP2S1 介导的 APP 降解和转位调节。在 AD 动物模型 APP/PS1 小鼠中，AAV 介导的 AP2S1 shRNA 在海马体中的递送显着降低了 APP 和 Aβ 的蛋白质水平，伴随着 APP 转位、LE-溶血融合和改善的认知功能。总之，这些数据揭示了 APP 降解中的 LE-溶血融合机制，并表明 AP2S1 在 AD 的病理生理学中的新作用。随着伴随的 APP translocalization、LE-lyso 融合和改善的认知功能。总之，这些数据揭示了 APP 降解中的 LE-溶血融合机制，并表明 AP2S1 在 AD 的病理生理学中的新作用。随着伴随的 APP translocalization、LE-lyso 融合和改善的认知功能。总之，这些数据揭示了 APP 降解中的 LE-溶血融合机制，并表明 AP2S1 在 AD 的病理生理学中的新作用。

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AP2S1 regulates APP degradation through late endosome–lysosome fusion in cells and APP/PS1 mice

AP2S1 is the sigma 2 subunit of adaptor protein 2 (AP2) that is essential for endocytosis. In this study, we investigated the potential role of AP2S1 in intracellular processing of amyloid precursor protein (APP), which contributes to the pathogenesis of Alzheimer disease (AD) by generating the toxic β-amyloid peptide (Aβ). We found that knockdown or overexpression of AP2S1 decreased or increased the protein levels of APP and Aβ in cells stably expressing human full-length APP695, respectively. This effect was unrelated to endocytosis but involved lysosomal degradation. Morphological studies revealed that silencing of AP2S1 promoted the translocalization of APP from RAB9-positive late endosomes (LE) to LAMP1-positive lysosomes, which was paralleled by the enhanced LE-lysosome fusion. In support, silencing of vacuolar protein sorting-associated protein 41 (VPS41) that is implicated in LE-lyso fusion prevented AP2S1-mediated regulation of APP degradation and translocalization. In APP/PS1 mice, an animal model of AD, AAV-mediated delivery of AP2S1 shRNA in the hippocampus significantly reduced the protein levels of APP and Aβ, with the concomitant APP translocalization, LE-lyso fusion and the improved cognitive functions. Taken together, these data uncover a LE-lyso fusion mechanism in APP degradation and suggest a novel role for AP2S1 in the pathophysiology of AD.

更新日期：2022-11-22

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