E674Q(Shanghai APP mutant),a novel amyloid precursor protein mutation,in familial late-onset Alzheimer's disease  

作　　者：Yongfang Zhang Xinyi Xie Boyu Chen Lina Pan Jianping Li Wanbing Wang Jintao Wang Ran Tang Qiang Huang Xiaofen Chen Rujing Ren Zhentao Zhang Wei Fu Gang Wang 

机构地区：[1]Department of Neurology,Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [2]Department of Pharmacology and Chemical Biology,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [3]Department of Medicinal Chemistry,School of Pharmacy,Fudan University,Shanghai 201203,China [4]Department of Neurology,Renmin Hospital of Wuhan University,Wuhan,Hubei 430060,China [5]Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research,Institute of Neuroscience,School of Medicine,Xiamen University,Xiamen,Fujian 361102,China [6]Shenzhen Research Institute of Xiamen University,Shenzhen,Guangdong 518063,China

出　　处：《Genes & Diseases》2024年第2期1022-1034,共13页基因与疾病（英文）

基　　金：supported by grants from the Ministry of Science and Technology of the People's Republic of China(No.2021ZD020180);the Natural Science Foundation of China(No.81971068,81922021,81773635,82073765).

摘　　要：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 amyloidβdeposition was demonstrated in 18 F-florbetapir Positron Emission Tomography(PET).APP E674Q is close to theβ-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.

关 键 词：Alzheimer's disease Amyloid beta APP mutation E674Q Late onset 

分 类 号：R749.16[医药卫生—神经病学与精神病学]