title: Using Human iPSC-Derived Neurons to Model TAU Aggregation.
abstract: Alzheimer's disease and frontotemporal dementia are amongst the most common forms of dementia characterized by the formation and deposition of abnormal TAU in the brain. In order to develop a translational human TAU aggregation model suitable for screening, we transduced TAU harboring the pro-aggregating P301L mutation into control hiPSC-derived neural progenitor cells followed by differentiation into cortical neurons. TAU aggregation and phosphorylation was quantified using AlphaLISA technology. Although no spontaneous aggregation was observed upon expressing TAU-P301L in neurons, seeding with preformed aggregates consisting of the TAU-microtubule binding repeat domain triggered robust TAU aggregation and hyperphosphorylation already after 2 weeks, without affecting general cell health. To validate our model, activity of two autophagy inducers was tested. Both rapamycin and trehalose significantly reduced TAU aggregation levels suggesting that iPSC-derived neurons allow for the generation of a biologically relevant human Tauopathy model, highly suitable to screen for compounds that modulate TAU aggregation.
authors.affiliation: Janssen Research & Development, a division of Janssen Pharmaceutica N.V, Beerse, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Verheyen
authors.affiliation: Janssen Research & Development, a division of Janssen Pharmaceutica N.V, Beerse, Belgium.
authors.forename: Annick
authors.initials: A
authors.lastname: Diels
authors.affiliation: Janssen Research & Development, a division of Janssen Pharmaceutica N.V, Beerse, Belgium.
authors.forename: Joyce
authors.initials: J
authors.lastname: Dijkmans
authors.affiliation: Janssen Research & Development, a division of Janssen Pharmaceutica N.V, Beerse, Belgium.
authors.forename: Tutu
authors.initials: T
authors.lastname: Oyelami
authors.affiliation: Janssen Research & Development, a division of Janssen Pharmaceutica N.V, Beerse, Belgium.
authors.forename: Giulia
authors.initials: G
authors.lastname: Meneghello
authors.affiliation: Janssen Research & Development, a division of Janssen Pharmaceutica N.V, Beerse, Belgium.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Mertens
authors.affiliation: Janssen Research & Development, a division of Janssen Pharmaceutica N.V, Beerse, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Versweyveld
authors.affiliation: Janssen Research & Development, a division of Janssen Pharmaceutica N.V, Beerse, Belgium.
authors.forename: Marianne
authors.initials: M
authors.lastname: Borgers
authors.affiliation: Janssen Research & Development, a division of Janssen Pharmaceutica N.V, Beerse, Belgium.
authors.forename: Arjan
authors.initials: A
authors.lastname: Buist
authors.affiliation: Janssen Research & Development, a division of Janssen Pharmaceutica N.V, Beerse, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Peeters
authors.affiliation: Janssen Research & Development, a division of Janssen Pharmaceutica N.V, Beerse, Belgium.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Cik
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D001343:Autophagy / Q000502:physiology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D006801:Humans; D008954:Models, Biological; D009154:Mutation / Q000502:physiology; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D066263:Protein Aggregation, Pathological / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding / Q000502:physiology; D024801:Tauopathies / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins