title: The Dynamics and Turnover of Tau Aggregates in Cultured Cells: INSIGHTS INTO THERAPIES FOR TAUOPATHIES.
abstract: Filamentous tau aggregates, the hallmark lesions of Alzheimer disease (AD), play key roles in neurodegeneration. Activation of protein degradation systems has been proposed to be a potential strategy for removing pathological tau, but it remains unclear how effectively tau aggregates can be degraded by these systems. By applying our previously established cellular model system of AD-like tau aggregate induction using preformed tau fibrils, we demonstrate that tau aggregates induced in cells with regulated expression of full-length mutant tau can be gradually cleared when soluble tau expression is suppressed. This clearance is at least partially mediated by the autophagy-lysosome pathway, although both the ubiquitin-proteasome system and the autophagy-lysosome pathway are deficient in handling large tau aggregates. Importantly, residual tau aggregates left after the clearance phase leads to a rapid reinstatement of robust tau pathology once soluble tau expression is turned on again. Moreover, we succeeded in generating monoclonal cells persistently carrying tau aggregates without obvious cytotoxicity. Live imaging of GFP-tagged tau aggregates showed that tau inclusions are dynamic structures constantly undergoing "fission" and "fusion," which facilitate stable propagation of tau pathology in dividing cells. These findings provide a greater understanding of cell-to-cell transmission of tau aggregates in dividing cells and possibly neurons.
authors.affiliation: From the Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 and guojing@mail.med.upenn.edu.
authors.forename: Jing L
authors.initials: JL
authors.lastname: Guo
authors.affiliation: the Neuroscience Department, Janssen Research and Development, a Division of Janssen Pharmaceutica NV, 2340 Beerse, Belgium.
authors.forename: Arjan
authors.initials: A
authors.lastname: Buist
authors.affiliation: the Neuroscience Department, Janssen Research and Development, a Division of Janssen Pharmaceutica NV, 2340 Beerse, Belgium.
authors.forename: Alberto
authors.initials: A
authors.lastname: Soares
authors.affiliation: the Neuroscience Department, Janssen Research and Development, a Division of Janssen Pharmaceutica NV, 2340 Beerse, Belgium.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Callaerts
authors.affiliation: the Neuroscience Department, Janssen Research and Development, a Division of Janssen Pharmaceutica NV, 2340 Beerse, Belgium.
authors.forename: Sara
authors.initials: S
authors.lastname: Calafate
authors.affiliation: the Neuroscience Department, Janssen Research and Development, a Division of Janssen Pharmaceutica NV, 2340 Beerse, Belgium.
authors.forename: Frederik
authors.initials: F
authors.lastname: Stevenaert
authors.affiliation: From the Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 and.
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Daniels
authors.affiliation: From the Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 and.
authors.forename: Bryan E
authors.initials: BE
authors.lastname: Zoll
authors.affiliation: From the Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 and.
authors.forename: Alex
authors.initials: A
authors.lastname: Crowe
authors.affiliation: From the Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 and.
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Brunden
authors.affiliation: the Neuroscience Department, Janssen Research and Development, a Division of Janssen Pharmaceutica NV, 2340 Beerse, Belgium.
authors.forename: Diederik
authors.initials: D
authors.lastname: Moechars
authors.affiliation: From the Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 and vmylee@upenn.edu.
authors.forename: Virginia M Y
authors.initials: VM
authors.lastname: Lee
mesh_terms: D001343:Autophagy; D002460:Cell Line; D006801:Humans; D007700:Kinetics; D008247:Lysosomes / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D066329:Protein Aggregates; D059748:Proteolysis; D012995:Solubility; D024801:Tauopathies / Q000188:drug therapy; D054875:Ubiquitination; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; D066329:Protein Aggregates; D016875:tau Proteins; D046988:Proteasome Endopeptidase Complex
keywords: Alzheimer disease; autophagy; protein aggregation; protein degradation; tau protein (tau)