Removing endogenous tau does not prevent tau propagation yet reduces its neurotoxicity |
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Authors: | Susanne Wegmann Eduardo A Maury Molly J Kirk Lubna Saqran Allyson Roe Sarah L DeVos Samantha Nicholls Zhanyun Fan Shuko Takeda Ozge Cagsal‐Getkin Christopher M William Tara L Spires‐Jones Rose Pitstick George A Carlson Amy M Pooler Bradley T Hyman |
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Affiliation: | 1. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA;2. Centre for Cognitive and Neural Systems and Euan MacDonald Centre, University of Edinburgh, Edinburgh, UK;3. McLaughlin Research Institute, Great Falls, MT, USA;4. Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK |
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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. |
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Keywords: | Alzheimer's disease neurodegeneration neurofibrillary tangles P301L tau prion‐like |
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