title: Early pathogenic event of Alzheimer's disease documented in iPSCs from patients with PSEN1 mutations.
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.
authors.affiliation: 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.
authors.forename: Juan
authors.initials: J
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Hanzhi
authors.initials: H
authors.lastname: Zhao
authors.affiliation: 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.|Shanghai Stem Cell Institute, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ma
authors.affiliation: 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.
authors.forename: Guilai
authors.initials: G
authors.lastname: Shi
authors.affiliation: 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.
authors.forename: Jian
authors.initials: J
authors.lastname: Song
authors.affiliation: 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.
authors.forename: Yu
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Center for Clinical Research on Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian 116021, China.
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.affiliation: Institute of Neuroscience, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Liu
authors.affiliation: 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.|Shanghai Stem Cell Institute, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Tang
authors.affiliation: 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.|Shanghai Stem Cell Institute, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Gu
authors.affiliation: 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.
authors.forename: Lingling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Institute of Precision Medicine, The Xiangya Hospital, State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha 410078, China.
authors.forename: Zhuohua
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Institute of Neuroscience, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhang
authors.affiliation: 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.|Shanghai Stem Cell Institute, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jin
authors.affiliation: 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.|Center for Clinical Research on Neurological Diseases, the First Affiliated Hospital, Dalian Medical University, Dalian 116021, China.|Institute of Neurology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200025, China.|Collaborative Innovation Center for Brain Science, the First Affiliated Hospital, Dalian Medical University, Dalian 116011, China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Le
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D017209:Apoptosis; D002460:Cell Line; D049109:Cell Proliferation; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D009154:Mutation; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology*; D055495:Neurogenesis; D010446:Peptide Fragments / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D053764:Presenilin-1 / Q000235:genetics*; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D005819:Genetic Markers; C054369:MAPT protein, human; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
keywords: Alzheimer’s disease; apoptosis; induced pluripotent stem cells; neural progenitor cells; premature neuronal differentiation