title: Induced pluripotent stem cells from familial Alzheimer's disease patients differentiate into mature neurons with amyloidogenic properties.
abstract: Although the majority of Alzheimer's disease (AD) cases are sporadic, about 5% of cases are inherited in an autosomal dominant pattern as familial AD (FAD) and manifest at an early age. Mutations in the presenilin 1 (PSEN1) gene account for the majority of early-onset FAD. Here, we describe the generation of virus-free human induced pluripotent stem cells (hiPSCs) derived from fibroblasts of patients harboring the FAD PSEN1 mutation A246E and fibroblasts from healthy age-matched controls using nonintegrating episomal vectors. We have differentiated these hiPSC lines to the neuronal lineage and demonstrated that hiPSC-derived neurons have mature phenotypic and physiological properties. Neurons from mutant hiPSC lines express PSEN1-A246E mutations themselves and show AD-like biochemical features, that is, amyloidogenic processing of amyloid precursor protein (APP) indicated by an increase in β-amyloid (Aβ)42/Aβ40 ratio. FAD hiPSCs harboring disease properties can be used as humanized models to test novel diagnostic methods and therapies and explore novel hypotheses for AD pathogenesis.
authors.affiliation: 1 Division of Neuropathology, Department of Pathology, Johns Hopkins University School of Medicine , Baltimore, Maryland.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Mahairaki
authors.forename: Jiwon
authors.initials: J
authors.lastname: Ryu
authors.forename: Ann
authors.initials: A
authors.lastname: Peters
authors.forename: Qing
authors.initials: Q
authors.lastname: Chang
authors.forename: Tong
authors.initials: T
authors.lastname: Li
authors.forename: Tea Soon
authors.initials: TS
authors.lastname: Park
authors.forename: Paul W
authors.initials: PW
authors.lastname: Burridge
authors.forename: Conover C
authors.initials: CC
authors.lastname: Talbot
authors.forename: Laura
authors.initials: L
authors.lastname: Asnaghi
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Martin
authors.forename: Elias T
authors.initials: ET
authors.lastname: Zambidis
authors.forename: Vassilis E
authors.initials: VE
authors.lastname: Koliatsos
mesh_terms: D000200:Action Potentials; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016022:Case-Control Studies; D002460:Cell Line; D002478:Cells, Cultured; D065150:Cellular Reprogramming; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D020125:Mutation, Missense; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology* / Q000378:metabolism / Q000502:physiology; D053764:Presenilin-1 / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; C508853:PSEN1 protein, human; D053764:Presenilin-1