title: Mobility and subcellular localization of endogenous, gene-edited Tau differs from that of over-expressed human wild-type and P301L mutant Tau.
abstract: Alzheimer's disease (AD) and a subset of frontotemporal dementia termed FTLD-Tau are characterized by a massive, yet incompletely characterized and understood redistribution of Tau. To establish a framework for understanding this pathology, we used the genome-editing tool TALEN and generated Tau-mEOS2 knock-in mice to determine the mobility and subcellular localization of endogenous Tau in hippocampal cultures. We analysed Tau in axons, dendrites and spines at three stages of maturation using live-cell imaging, photo-conversion and FRAP assays. Tau-mEOS2 cultures were compared with those over-expressing EGFP-tagged forms of human wild-type (hWT-Tau) and P301L mutant Tau (hP301L-Tau), modelling Tau accumulation in AD and FTLD-Tau, respectively. In developing neurons, Tau-mEOS2 followed a proximo-distal gradient in axons and a subcellular distribution similar to that of endogenous Tau in neurons obtained from wild-type mice, which were abolished, when either hWT-Tau or hP301L-Tau was over-expressed. For the three conditions, FRAP analysis revealed a similar mobility in dendrites compared with axons; however, Tau-mEOS2 was less mobile than hWT-Tau and hP301L-Tau and the mobile fraction was smaller, possibly reflecting less efficient microtubule binding of Tau when over-expressed. Together, our study presents Tau-mEOS2 mice as a novel tool for the study of Tau in a physiological and a pathological context.
authors.affiliation: Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St Lucia Campus, Brisbane, QLD 4072, Australia.
authors.forename: Di
authors.initials: D
authors.lastname: Xia
authors.affiliation: Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St Lucia Campus, Brisbane, QLD 4072, Australia.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Gutmann
authors.affiliation: Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, St Lucia Campus, Brisbane, QLD 4072, Australia.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Götz
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001369:Axons / Q000737:chemistry / Q000473:pathology; D003712:Dendrites / Q000737:chemistry / Q000473:pathology; D004195:Disease Models, Animal; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000473:pathology; D000072669:Gene Editing; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000737:chemistry / Q000473:pathology; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics*
chemical_list: D016875:tau Proteins