Presynaptic Vesicle Protein SEPTIN5 Regulates the Degradation of APP C-Terminal Fragments and the Levels of Aβ.
Presynaptic Vesicle Protein SEPTIN5 Regulates the Degradation of APP C-Terminal Fragments and the Levels of Aβ.
复制标题
突触前囊泡蛋白SEPTIN5调节APP C末端片段的降解和Aβ的水平。
DOI：
10.3390/cells9112482
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发表时间：
2020-11-15
期刊：
影响因子：
6
通讯作者：
Hiltunen M
中科院分区：
文献类型：
--
作者：
Marttinen M;Ferreira CB;Paldanius KMA;Takalo M;Natunen T;Mäkinen P;Leppänen L;Leinonen V;Tanigaki K;Kang G;Hiroi N;Soininen H;Rilla K;Haapasalo A;Hiltunen M
阿尔茨海默病（Alzheimer's disease，AD）是一种以异常β淀粉样蛋白（amyloid-β，Aβ）和过度磷酸化tau蛋白聚集为特征的神经退行性疾病。我们以前研究了SEPTIN家族成员参与AD相关细胞过程，并发现SEPTIN 8在β-分泌酶的分选和积累中的作用。在这里，我们阐明了SEPTIN 5（SEPTIN 8的相互作用伙伴）在与AD相关的细胞过程中的潜在作用，包括淀粉样前体蛋白（APP）加工和Aβ的产生。体外和体内研究均显示，SEPTIN 5的下调降低了神经元细胞和Septin 5敲除小鼠皮质中APP C末端片段（APP CTF）和Aβ的水平。机制阐明表明，SEPTIN 5的下调增加了APP CTFs的降解，而不影响分泌途径相关的运输或内吞作用的APP。此外，我们发现，APP CTFs降解，在很大程度上，通过自噬体途径和SEPTIN 5的下调增强自噬体的活性在神经元细胞中的关键自噬体标记物的水平改变所示。总的来说，我们的数据表明SEPTIN 5的下调增加了APP CTF的自噬介导的降解，导致神经元细胞中Aβ水平降低。
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by aberrant amyloid-β (Aβ) and hyperphosphorylated tau aggregation. We have previously investigated the involvement of SEPTIN family members in AD-related cellular processes and discovered a role for SEPTIN8 in the sorting and accumulation of β-secretase. Here, we elucidated the potential role of SEPTIN5, an interaction partner of SEPTIN8, in the cellular processes relevant for AD, including amyloid precursor protein (APP) processing and the generation of Aβ. The in vitro and in vivo studies both revealed that the downregulation of SEPTIN5 reduced the levels of APP C-terminal fragments (APP CTFs) and Aβ in neuronal cells and in the cortex of Septin5 knockout mice. Mechanistic elucidation revealed that the downregulation of SEPTIN5 increased the degradation of APP CTFs, without affecting the secretory pathway-related trafficking or the endocytosis of APP. Furthermore, we found that the APP CTFs were degraded, to a large extent, via the autophagosomal pathway and that the downregulation of SEPTIN5 enhanced autophagosomal activity in neuronal cells as indicated by altered levels of key autophagosomal markers. Collectively, our data suggest that the downregulation of SEPTIN5 increases the autophagy-mediated degradation of APP CTFs, leading to reduced levels of Aβ in neuronal cells.
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影响因子：
5.3
作者：
Peng, XR;Jia, ZP;Trimble, WS
通讯作者：
Trimble, WS
影响因子：
11.2
作者：
Martiskainen, Henna;Herukka, Sanna-Kaisa;Hiltunen, Mikko
通讯作者：
Hiltunen, Mikko
影响因子：
4.7
作者：
Son, JH;Kawamata, H;Peng, C
通讯作者：
Peng, C
影响因子：
1.2
作者：
Gómez-Sánchez R;Yakhine-Diop SM;Rodríguez-Arribas M;Bravo-San Pedro JM;Martínez-Chacón G;Uribe-Carretero E;Pinheiro de Castro DC;Pizarro-Estrella E;Fuentes JM;González-Polo RA
通讯作者：
González-Polo RA
DOI：
10.1111/j.1600-0854.2010.01149.x
发表时间：
2011-03
期刊：
Traffic (Copenhagen, Denmark)
影响因子：
--
作者：
Viswanathan J;Haapasalo A;Böttcher C;Miettinen R;Kurkinen KM;Lu A;Thomas A;Maynard CJ;Romano D;Hyman BT;Berezovska O;Bertram L;Soininen H;Dantuma NP;Tanzi RE;Hiltunen M
通讯作者：
Hiltunen M