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

// Juan Yang 1, * , Hanzhi Zhao 1, * , Yu Ma 1, 2 , Guilai Shi 1 , Jian Song 1 , Yu Tang 1 , Song Li 3 , Ting Li 1 , Nan Liu 4 , Fan Tang 1, 2 , Junjie Gu 1, 2 , Lingling Zhang 1 , Zhuohua Zhang 5 , Xiaohui Zhang 4 , Ying Jin 1, 2 , Weidong Le 1, 3, 6, 7 1 Key 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 2 Shanghai Stem Cell Institute, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China 3 Center for Clinical Research on Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian 116021, China 4 Institute of Neuroscience, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China 5 Institute of Precision Medicine, The Xiangya Hospital, State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha 410078, China 6 Institute of Neurology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China 7 Collaborative 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: wdle@sibs.ac.cn Ying Jin, email: yjin@sibs.ac.cn 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 Aβ 42 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.