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

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

doi:10.1016/j.gendis.2023.02.051

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

Full-length article | 更新时间：2024-02-04

- 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
- Genes & Diseases 2024年11卷第2期
- 作者机构：
  
  1. Department of Neurology, Renmin Hospital of Wuhan University,Hubei,Wuhan,China,430060
  2. Department of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai,China,200025
  3. Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University,Fujian,Xiamen,China,361102
  4. Department of Medicinal Chemistry, School of Pharmacy, Fudan University,Shanghai,China,201203
  5. Shenzhen Research Institute of Xiamen University,Guangdong,Shenzhen,China,518063
  6. Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine,Shanghai,China,200025
- 作者简介：
- 基金信息：
- DOI：10.1016/j.gendis.2023.02.051
  中图分类号：
- 纸质出版日期：2024，
  
  网络出版日期：2024-3-1，
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Yongfang Zhang, Xinyi Xie, Boyu Chen, 等. E674Q (Shanghai APP mutant), a novel amyloid precursor protein mutation, in familial late-onset Alzheimer's disease[J]. Genes & Diseases, 2024,11(2).

Yongfang Zhang, Xinyi Xie, Boyu Chen, et al. E674Q (Shanghai APP mutant), a novel amyloid precursor protein mutation, in familial late-onset Alzheimer's disease[J]. Genes & Diseases, 2024,11(2).
Yongfang Zhang, Xinyi Xie, Boyu Chen, 等. E674Q (Shanghai APP mutant), a novel amyloid precursor protein mutation, in familial late-onset Alzheimer's disease[J]. Genes & Diseases, 2024,11(2). DOI： 10.1016/j.gendis.2023.02.051.

Yongfang Zhang, Xinyi Xie, Boyu Chen, et al. E674Q (Shanghai APP mutant), a novel amyloid precursor protein mutation, in familial late-onset Alzheimer's disease[J]. Genes & Diseases, 2024,11(2). DOI： 10.1016/j.gendis.2023.02.051.

摘要

Abstract

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

F-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.

关键词

Keywords

Alzheimer's diseaseAmyloid betaAPP mutationE674QLate onset

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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

DOI：10.1016/j.gendis.2023.02.051

摘要

Abstract

关键词

Keywords

references