Oncotarget

Research Papers:

Early pathogenic event of Alzheimer's disease documented in iPSCs from patients with PSEN1 mutations

Juan Yang _, Hanzhi Zhao, Yu Ma, Guilai Shi, Jian Song, Yu Tang, Song Li, Ting Li, Nan Liu, Fan Tang, Junjie Gu, Lingling Zhang, Zhuohua Zhang, Xiaohui Zhang, Ying Jin and Weidong Le

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Oncotarget. 2017; 8:7900-7913. https://doi.org/10.18632/oncotarget.13776

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Abstract

Juan Yang1,*, Hanzhi Zhao1,*, Yu Ma1,2, Guilai Shi1, Jian Song1, Yu Tang1, Song Li3, Ting Li1, Nan Liu4, Fan Tang1,2, Junjie Gu1,2, Lingling Zhang1, Zhuohua Zhang5, Xiaohui Zhang4, Ying Jin1,2, Weidong Le1,3,6,7

1Key Laboratory of Stem Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai JiaoTong University School of Medicine, Shanghai 200031, China

2Shanghai Stem Cell Institute, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China

3Center for Clinical Research on Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian 116021, China

4Institute of Neuroscience, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China

5Institute of Precision Medicine, The Xiangya Hospital, State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha 410078, China

6Institute of Neurology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China

7Collaborative Innovation Center for Brain Science, the First Affiliated Hospital, Dalian Medical University, Dalian 116011, China

*These authors have contributed equally to this work

Correspondence to:

Weidong Le, email: [email protected]

Ying Jin, email: [email protected]

Keywords: Alzheimer’s disease, apoptosis, neural progenitor cells, premature neuronal differentiation, induced pluripotent stem cells

Received: September 30, 2016     Accepted: November 21, 2016     Published: December 02, 2016

ABSTRACT

Alzheimer’s disease (AD) is the most common age-related dementia characterized by progressive neuronal loss. However, the molecular mechanisms for the neuronal loss is still debated. Here, we used induced pluripotent stem cells (iPSCs) derived from somatic cells of familial AD patients carrying PSEN1 mutations to study the early pathogenic event of AD. We found that premature neuronal differentiation with decreased proliferation and increased apoptosis occured in AD-iPSC-derived neural progenitor cells (AD-NPCs) once neuronal differentiation was initiated, together with higher levels of Aβ42 and phosphorylated tau. Premature neuronal differentiation in AD-NPCs was caused by PSEN1 mutations and might be correlated to multiple dysregulated processes including but not limited to Wnt-Notch pathway. Our study documented previously unappreciated early NPC dysfunction in AD-NPCs, providing valuable new insights into the early mechanisms underlying AD pathogenesis.


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