E674Q (Shanghai APP 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

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

Genes Dis. 2023 Apr 10;11(2):1022-1034. doi: 10.1016/j.gendis.2023.02.051. eCollection 2024 Mar.

Authors

Yongfang Zhang^{1

2}, Xinyi Xie¹, Boyu Chen³, Lina Pan⁴, Jianping Li¹, Wanbing Wang^{5

6}, Jintao Wang¹, Ran Tang¹, Qiang Huang¹, Xiaofen Chen^{5

6}, Rujing Ren¹, Zhentao Zhang⁴, Wei Fu³, Gang Wang¹

Affiliations

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.

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 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.

Keywords: APP mutation; Alzheimer's disease; Amyloid beta; E674Q; Late onset.