title: Removing endogenous tau does not prevent tau propagation yet reduces its neurotoxicity.
abstract: In Alzheimer's disease and tauopathies, tau protein aggregates into neurofibrillary tangles that progressively spread to synaptically connected brain regions. A prion-like mechanism has been suggested: misfolded tau propagating through the brain seeds neurotoxic aggregation of soluble tau in recipient neurons. We use transgenic mice and viral tau expression to test the hypotheses that trans-synaptic tau propagation, aggregation, and toxicity rely on the presence of endogenous soluble tau. Surprisingly, mice expressing human P301Ltau in the entorhinal cortex showed equivalent tau propagation and accumulation in recipient neurons even in the absence of endogenous tau. We then tested whether the lack of endogenous tau protects against misfolded tau aggregation and toxicity, a second prion model paradigm for tau, using P301Ltau-overexpressing mice with severe tangle pathology and neurodegeneration. Crossed onto tau-null background, these mice had similar tangle numbers but were protected against neurotoxicity. Therefore, misfolded tau can propagate across neural systems without requisite templated misfolding, but the absence of endogenous tau markedly blunts toxicity. These results show that tau does not strictly classify as a prion protein.
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors.forename: Susanne
authors.initials: S
authors.lastname: Wegmann
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: Maury
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors.forename: Molly J
authors.initials: MJ
authors.lastname: Kirk
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors.forename: Lubna
authors.initials: L
authors.lastname: Saqran
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors.forename: Allyson
authors.initials: A
authors.lastname: Roe
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: DeVos
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Nicholls
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors.forename: Zhanyun
authors.initials: Z
authors.lastname: Fan
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors.forename: Shuko
authors.initials: S
authors.lastname: Takeda
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors.forename: Ozge
authors.initials: O
authors.lastname: Cagsal-Getkin
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: William
authors.affiliation: Centre for Cognitive and Neural Systems and Euan MacDonald Centre, University of Edinburgh, Edinburgh, UK.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Spires-Jones
authors.affiliation: McLaughlin Research Institute, Great Falls, MT, USA.
authors.forename: Rose
authors.initials: R
authors.lastname: Pitstick
authors.affiliation: McLaughlin Research Institute, Great Falls, MT, USA.
authors.forename: George A
authors.initials: GA
authors.lastname: Carlson
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Pooler
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA bhyman@mgh.harvard.edu.
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D018728:Entorhinal Cortex / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020125:Mutation, Missense; D009474:Neurons / Q000378:metabolism; D016875:tau Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: C558298:Mapt protein, mouse; D016875:tau Proteins
keywords: Alzheimer's disease; P301L tau; neurodegeneration; neurofibrillary tangles; prion‐like