E674Q (Shanghai APP mutant), a novel amyloid precursor protein mutation, in familial late-onset Alzheimer's disease.
E674Q (Shanghai APP mutant), a novel amyloid precursor protein mutation, in familial late-onset Alzheimer's disease.
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DOI：
10.1016/j.gendis.2023.02.051
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发表时间：
2024-03
期刊：
影响因子：
6.8
通讯作者：
Wang, Gang
中科院分区：
文献类型：
--
作者：
Zhang, Yongfang;Xie, Xinyi;Chen, Boyu;Pan, Lina;Li, Jianping;Wang, Wanbing;Wang, Jintao;Tang, Ran;Huang, Qiang;Chen, Xiaofen;Ren, Rujing;Zhang, Zhentao;Fu, Wei;Wang, Gang
APP、PSEN1、PSEN2被确定为阿尔茨海默病（Alzheimer's disease， AD）的致病基因，主要导致早发性AD，病程更具侵袭性，非典型症状较散发性AD更为常见。本研究中，一种新的错义突变APP E674Q（也被称为“Shanghai APP”）在一名典型晚发型AD （LOAD）的中国指数患者中被检测到，该患者在70多岁中期出现记忆衰退。神经影像学结果与AD一致，18F-florbetapir正电子发射断层扫描（PET）显示广泛的β淀粉样蛋白沉积。APP E674Q靠近β分泌酶切割位点和瑞典APP突变（KM670/671NL），该突变被预测为硅致病性。分子动力学模拟表明，E674Q突变导致APP与BACE1相互作用模式重排，E674Q突变更容易被BACE1切割。体外实验结果表明，E674Q突变通过促进bace1介导的APP加工和Aβ的产生而致病。此外，我们应用腺相关病毒（AAV）介导的人类E674Q突变体APP基因转移到两个月大的C57Bl/6 J小鼠的海马。注射aav -E674Q的小鼠表现出学习行为受损和大脑病理负担增加，这意味着E674Q突变具有与经典瑞典突变相比的致病性。总的来说，我们报告了AD中E674Q取代的强烈淀粉样变性作用。据我们所知，E674Q是淀粉样蛋白加工序列中唯一引起LOAD的致病突变。
Identified as the pathogenic genes of Alzheimer's disease (AD), APP, PSEN1, and PSEN2 mainly lead to early-onset AD, whose course is more aggressive, and atypical symptoms are more common than sporadic AD. Here, a novel missense mutation, APP E674Q (also named “Shanghai APP”), was detected in a Chinese index patient with typical late-onset AD (LOAD) who developed memory decline in his mid-70s. The results from neuroimaging were consistent with AD, where widespread amyloid β deposition was demonstrated in 18F-florbetapir Positron Emission Tomography (PET). APP E674Q is close to the β-secretase cleavage site and the well-studied Swedish APP mutation (KM670/671NL), which was predicted to be pathogenic in silico. Molecular dynamics simulation indicated that the E674Q mutation resulted in a rearrangement of the interaction mode between APP and BACE1 and that the E674Q mutation was more prone to cleavage by BACE1. The in vitro results suggested that the E674Q mutation was pathogenic by facilitating the BACE1-mediated processing of APP and the production of Aβ. Furthermore, we applied an adeno-associated virus (AAV)-mediated transfer of the human E674Q mutant APP gene to the hippocampi of two-month-old C57Bl/6 J mice. AAV-E674Q-injected mice exhibited impaired learning behavior and increased pathological burden in the brain, implying that the E674Q mutation had a pathogenicity that bore a comparison with the classical Swedish mutation. Collectively, we report a strong amyloidogenic effect of the E674Q substitution in AD. To our knowledge, E674Q is the only pathogenic mutation within the amyloid processing sequence causing LOAD.
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DOI：
10.1016/j.jalz.2011.03.005
发表时间：
2011-05
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
McKhann GM;Knopman DS;Chertkow H;Hyman BT;Jack CR Jr;Kawas CH;Klunk WE;Koroshetz WJ;Manly JJ;Mayeux R;Mohs RC;Morris JC;Rossor MN;Scheltens P;Carrillo MC;Thies B;Weintraub S;Phelps CH
通讯作者：
Phelps CH
影响因子：
14
作者：
通讯作者：
--
影响因子：
30.8
作者：
MULLAN, M;CRAWFORD, F;LANNFELT, L
通讯作者：
LANNFELT, L
影响因子：
48
作者：
Tang, Mengxuan;Ryman, Davis C.;McDade, Eric;Jasielec, Mateusz S.;Buckles, Virginia D.;Cairns, Nigel J.;Fagan, Anne M.;Goate, Alison;Marcus, Daniel S.;Xiong, Chengjie;Allegri, Ricardo F.;Chhatwal, Jasmeer P.;Danek, Adrian;Farlow, Martin R.;Fox, Nick C.;Ghetti, Bernardino;Graff-Radford, Neill R.;Laske, Christopher;Martins, Ralph N.;Masters, Colin L.;Mayeux, Richard P.;Ringman, John M.;Rossor, Martin N.;Salloway, Stephen P.;Schofield, Peter R.;Morris, John C.;Bateman, Randall J.
通讯作者：
Bateman, Randall J.
影响因子：
4.2
作者：
Guerreiro, Rita Joao;Baquero, Miguel;Blesa, Rafael;Boada, Merce;Bras, Jose Miguel;Bullido, Maria J.;Calado, Ana;Crook, Richard;Ferreira, Carla;Frank, Ana;Gomez-Isla, Teresa;Hernandez, Isabel;Lleo, Alberto;Machado, Alvaro;Martinez-Lage, Pablo;Masdeu, Jose;Molina-Porcel, Laura;Molinuevo, Jose L.;Pastor, Pau;Perez-Tur, Jordi;Relvas, Rute;Oliveira, Catarina Resende;Ribeiro, Maria Helena;Rogaeva, Ekaterina;Sa, Alfredo;Samaranch, Lluis;Sanchez-Valle, Raquel;Santana, Isabel;Tarraga, Lluis;Valdivieso, Fernando;Singleton, Andrew;Hardy, John;Clarimon, Jordi
通讯作者：
Clarimon, Jordi