E674Q (Shanghai APP mutant), a novel amyloid precursor protein mutation, in familial late-onset Alzheimer's disease
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...
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KeAi Communications Co., Ltd.
2024-03-01
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| Series: | Genes and Diseases |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352304223001277 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yongfang Zhang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T11:53:06Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2352-3042 |
| language | English |
| last_indexed | 2024-03-12T11:53:06Z |
| publishDate | 2024-03-01 |
| publisher | KeAi Communications Co., Ltd. |
| record_format | Article |
| series | Genes and Diseases |
| spelling | doaj.art-f6ef70830a114d649c495157fb8276f52023-08-31T05:03:04ZengKeAi Communications Co., Ltd.Genes and Diseases2352-30422024-03-0111210221034E674Q (Shanghai APP mutant), a novel amyloid precursor protein mutation, in familial late-onset Alzheimer's diseaseYongfang Zhang0Xinyi Xie1Boyu Chen2Lina Pan3Jianping Li4Wanbing Wang5Jintao Wang6Ran Tang7Qiang Huang8Xiaofen Chen9Rujing Ren10Zhentao Zhang11Wei Fu12Gang Wang13Department of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, ChinaDepartment of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, ChinaDepartment of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, ChinaDepartment of Neurology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, ChinaDepartment of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, ChinaFujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China; Shenzhen Research Institute of Xiamen University, Shenzhen, Guangdong 518063, ChinaDepartment of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, ChinaDepartment of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, ChinaDepartment of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, ChinaFujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China; Shenzhen Research Institute of Xiamen University, Shenzhen, Guangdong 518063, ChinaDepartment of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, ChinaDepartment of Neurology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China; Corresponding author.Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China; Corresponding author.Department of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S2352304223001277Alzheimer's diseaseAmyloid betaAPP mutationE674QLate onset |
| spellingShingle | 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 E674Q (Shanghai APP mutant), a novel amyloid precursor protein mutation, in familial late-onset Alzheimer's disease Genes and Diseases Alzheimer's disease Amyloid beta APP mutation E674Q Late onset |
| title | E674Q (Shanghai APP mutant), a novel amyloid precursor protein mutation, in familial late-onset Alzheimer's disease |
| title_full | E674Q (Shanghai APP mutant), a novel amyloid precursor protein mutation, in familial late-onset Alzheimer's disease |
| title_fullStr | E674Q (Shanghai APP mutant), a novel amyloid precursor protein mutation, in familial late-onset Alzheimer's disease |
| title_full_unstemmed | E674Q (Shanghai APP mutant), a novel amyloid precursor protein mutation, in familial late-onset Alzheimer's disease |
| title_short | E674Q (Shanghai APP mutant), a novel amyloid precursor protein mutation, in familial late-onset Alzheimer's disease |
| title_sort | e674q shanghai app mutant a novel amyloid precursor protein mutation in familial late onset alzheimer s disease |
| topic | Alzheimer's disease Amyloid beta APP mutation E674Q Late onset |
| url | http://www.sciencedirect.com/science/article/pii/S2352304223001277 |
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