title: Early maturation and distinct tau pathology in induced pluripotent stem cell-derived neurons from patients with MAPT mutations.
abstract: Tauopathies, such as Alzheimer's disease, some cases of frontotemporal dementia, corticobasal degeneration and progressive supranuclear palsy, are characterized by aggregates of the microtubule-associated protein tau, which are linked to neuronal death and disease development and can be caused by mutations in the MAPT gene. Six tau isoforms are present in the adult human brain and they differ by the presence of 3(3R) or 4(4R) C-terminal repeats. Only the shortest 3R isoform is present in foetal brain. MAPT mutations found in human disease affect tau binding to microtubules or the 3R:4R isoform ratio by altering exon 10 splicing. We have differentiated neurons from induced pluripotent stem cells derived from fibroblasts of controls and patients with N279K and P301L MAPT mutations. Induced pluripotent stem cell-derived neurons recapitulate developmental tau expression, showing the adult brain tau isoforms after several months in culture. Both N279K and P301L neurons exhibit earlier electrophysiological maturation and altered mitochondrial transport compared to controls. Specifically, the N279K neurons show abnormally premature developmental 4R tau expression, including changes in the 3R:4R isoform ratio and AT100-hyperphosphorylated tau aggregates, while P301L neurons are characterized by contorted processes with varicosity-like structures, some containing both alpha-synuclein and 4R tau. The previously unreported faster maturation of MAPT mutant human neurons, the developmental expression of 4R tau and the morphological alterations may contribute to disease development.
authors.affiliation: 1 Department of Clinical Neurosciences, Clifford Allbutt Building, University of Cambridge, Cambridge, UK.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Iovino
authors.affiliation: 2 Wellcome-Trust Medical Research Council Stem Cell Institute and Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Agathou
authors.affiliation: 3 Department of Physiology, Development and Neuroscience, Physiological Laboratory, University of Cambridge, Cambridge, UK.
authors.forename: Ana
authors.initials: A
authors.lastname: González-Rueda
authors.affiliation: 4 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Del Castillo Velasco-Herrera
authors.affiliation: 5 Department of Neurological Sciences, University of Brescia, Brescia, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Borroni
authors.affiliation: 5 Department of Neurological Sciences, University of Brescia, Brescia, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Alberici
authors.affiliation: 6 Dublin Neurological Institute, Mater Misericordiae University Hospital and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin Ireland.
authors.forename: Timothy
authors.initials: T
authors.lastname: Lynch
authors.affiliation: 6 Dublin Neurological Institute, Mater Misericordiae University Hospital and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin Ireland.
authors.forename: Sean
authors.initials: S
authors.lastname: O'Dowd
authors.affiliation: 7 Wellcome Trust-Medical Research Council Stem Cell Institute, Anne McLaren Laboratory, Department of Surgery, University of Cambridge, Cambridge UK.
authors.forename: Imbisaat
authors.initials: I
authors.lastname: Geti
authors.affiliation: 4 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gaffney
authors.affiliation: 4 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK 7 Wellcome Trust-Medical Research Council Stem Cell Institute, Anne McLaren Laboratory, Department of Surgery, University of Cambridge, Cambridge UK.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Vallier
authors.affiliation: 3 Department of Physiology, Development and Neuroscience, Physiological Laboratory, University of Cambridge, Cambridge, UK.
authors.forename: Ole
authors.initials: O
authors.lastname: Paulsen
authors.affiliation: 2 Wellcome-Trust Medical Research Council Stem Cell Institute and Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Ragnhildur Thóra
authors.initials: RT
authors.lastname: Káradóttir
authors.affiliation: 1 Department of Clinical Neurosciences, Clifford Allbutt Building, University of Cambridge, Cambridge, UK mgs11@cam.ac.uk.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Spillantini
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007150:Immunohistochemistry; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D007231:Infant, Newborn; D008297:Male; D018613:Microscopy, Confocal; D008870:Microtubules / Q000378:metabolism; D008875:Middle Aged; D009474:Neurons / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D018408:Patch-Clamp Techniques; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D024801:Tauopathies; D051844:alpha-Synuclein / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C054369:MAPT protein, human; D020033:Protein Isoforms; D012333:RNA, Messenger; D051844:alpha-Synuclein; D016875:tau Proteins
keywords: FTDP-17T; IPSC-derived neurons; MAPT gene mutations; microtubule-associated protein tau; neurofibrillary tangles