title: Characterization and molecular profiling of PSEN1 familial Alzheimer's disease iPSC-derived neural progenitors.
abstract: Presenilin 1 (PSEN1) encodes the catalytic subunit of γ-secretase, and PSEN1 mutations are the most common cause of early onset familial Alzheimer's disease (FAD). In order to elucidate pathways downstream of PSEN1, we characterized neural progenitor cells (NPCs) derived from FAD mutant PSEN1 subjects. Thus, we generated induced pluripotent stem cells (iPSCs) from affected and unaffected individuals from two families carrying PSEN1 mutations. PSEN1 mutant fibroblasts, and NPCs produced greater ratios of Aβ42 to Aβ40 relative to their control counterparts, with the elevated ratio even more apparent in PSEN1 NPCs than in fibroblasts. Molecular profiling identified 14 genes differentially-regulated in PSEN1 NPCs relative to control NPCs. Five of these targets showed differential expression in late onset AD/Intermediate AD pathology brains. Therefore, in our PSEN1 iPSC model, we have reconstituted an essential feature in the molecular pathogenesis of FAD, increased generation of Aβ42/40, and have characterized novel expression changes.
authors.affiliation: The New York Stem Cell Foundation, New York, New York, United States of America.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Sproul
authors.affiliation: The New York Stem Cell Foundation, New York, New York, United States of America.
authors.forename: Samson
authors.initials: S
authors.lastname: Jacob
authors.affiliation: Department of Pathology & Cell Biology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America.
authors.forename: Deborah
authors.initials: D
authors.lastname: Pre
authors.affiliation: Departments of Neurology and Psychiatry and the Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Soong Ho
authors.initials: SH
authors.lastname: Kim
authors.affiliation: The New York Stem Cell Foundation, New York, New York, United States of America.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Nestor
authors.affiliation: Department of Psychiatry, Columbia University, New York, New York, United States of America.
authors.forename: Miriam
authors.initials: M
authors.lastname: Navarro-Sobrino
authors.affiliation: Department of Pathology & Cell Biology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America.
authors.forename: Ismael
authors.initials: I
authors.lastname: Santa-Maria
authors.affiliation: The New York Stem Cell Foundation, New York, New York, United States of America.
authors.forename: Matthew
authors.initials: M
authors.lastname: Zimmer
authors.affiliation: Department of Pathology & Cell Biology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America.
authors.forename: Soline
authors.initials: S
authors.lastname: Aubry
authors.affiliation: Departments of Neurology and Psychiatry and the Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: John W
authors.initials: JW
authors.lastname: Steele
authors.affiliation: The New York Stem Cell Foundation, New York, New York, United States of America.
authors.forename: David J
authors.initials: DJ
authors.lastname: Kahler
authors.affiliation: Department of Psychiatry, Columbia University, New York, New York, United States of America.
authors.forename: Alex
authors.initials: A
authors.lastname: Dranovsky
authors.affiliation: Department of Pathology & Cell Biology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America.
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
authors.affiliation: Department of Pathology & Cell Biology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America.
authors.forename: John F
authors.initials: JF
authors.lastname: Crary
authors.affiliation: Departments of Neurology and Psychiatry and the Alzheimer's Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America ; James J Peters Veterans Administration Medical Center, Bronx, New York, United States of America.
authors.forename: Sam
authors.initials: S
authors.lastname: Gandy
authors.affiliation: The New York Stem Cell Foundation, New York, New York, United States of America.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Noggle
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D001921:Brain / Q000166:cytology / Q000473:pathology; D002454:Cell Differentiation; D002460:Cell Line; D005136:Eye Proteins / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D058953:Neural Stem Cells / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000473:pathology; D010446:Peptide Fragments / Q000096:biosynthesis; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics
chemical_list: C540562:ASB9 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D051017:Apoptosis Regulatory Proteins; D005136:Eye Proteins; C081848:NDP protein, human; C495732:NLRP2 protein, human; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D053764:Presenilin-1; D050826:Suppressor of Cytokine Signaling Proteins; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)