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

作者全名："Wen, Qi-Xin; Luo, Biao; Xie, Xiao-Yong; Zhou, Gui-Feng; Chen, Jian; Song, Li; Liu, Yue; Xie, Shi-Qi; Chen, Long; Li, Kun-Yi; Xiang, Xiao-Jiao; Chen, Guo-Jun"

作者地址："[Wen, Qi-Xin; Luo, Biao; Xie, Xiao-Yong; Zhou, Gui-Feng; Chen, Jian; Song, Li; Liu, Yue; Xie, Shi-Qi; Chen, Long; Li, Kun-Yi; Chen, Guo-Jun] Affiliated Hosp Chongqing Med Univ 1, Dept Neurol, Chongqing Key Lab Major Neurol & Mental Disorders, Chongqing Key Lab Neurol, Chongqing, Peoples R China; [Xiang, Xiao-Jiao] Affiliated Hosp Chongqing Med Univ 2, Dept Nucl Med, Chongqing, Peoples R China; [Chen, Guo-Jun] Chongqing Med Univ, Inst Brain Sci & Dis, Chongqing, Peoples R China; [Xiang, Xiao-Jiao] Affiliated Hosp Chongqing Med Univ 2, Dept Nucl Med, 74 Linjiang Rd, Chongqing 400010, Peoples R China; [Chen, Guo-Jun] Affiliated Hosp Chongqing Med Univ 1, Dept Neurol, Chongqing Key Lab Major Neurol & Mental Disorders, Chongqing Key Lab Neurol, 1 Youyi Rd, Chongqing 400016, Peoples R China"

通信作者："Xiang, XJ (通讯作者)，Affiliated Hosp Chongqing Med Univ 2, Dept Nucl Med, 74 Linjiang Rd, Chongqing 400010, Peoples R China.; Chen, GJ (通讯作者)，Affiliated Hosp Chongqing Med Univ 1, Dept Neurol, Chongqing Key Lab Major Neurol & Mental Disorders, Chongqing Key Lab Neurol, 1 Youyi Rd, Chongqing 400016, Peoples R China."

来源：TRAFFIC

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000898528200001

JCR分区：Q3

影响因子：4.5

年份：2023

卷号：24

期号：1

开始页：20

结束页：33

文献类型：Article

关键词：Adapter protein 2; Sigma subunit; Alzheimer disease; APP; A beta; Endosome-lysosome fusion

摘要："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 beta-amyloid peptide (A beta). We found that knockdown or overexpression of AP2S1 decreased or increased the protein levels of APP and A beta 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 A beta, 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."

基金机构："Chongqing Education Commission [KJZD-K201900404]; National Nature Science Foundation of China [81971030, 82201578]; Postgraduate Research and Innovation Project of Chongqing [CYB19146]"

基金资助正文："Chongqing Education Commission, Grant/Award Number: KJZD-K201900404; National Nature Science Foundation of China, Grant/Award Number: 81971030; Postgraduate Research and Innovation Project of Chongqing, Grant/Award Number: CYB19146; National Nature Science Foundation of China, Grant/Award Number: 82201578"