Removing endogenous tau does not prevent tau propagation yet reduces its neurotoxicity

Tara Spires-Jones, Susanne K Wegmann, Eduardo A Maury, Molly Kirk, Lubna Saqran, Allyson D Roe, Sarah DeVos

Research output: Contribution to journalArticlepeer-review


In Alzheimer's disease and tauopathies, tau protein aggregates into neurofibrillary tangles that progressively spread to synaptically connected brain regions. A prion-like mechanism for 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 absence of endogenous tau. We then tested if 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 numebrs 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.
Original languageEnglish
Pages (from-to)3028-3041
JournalEMBO Journal
Issue number24
Early online date4 Nov 2015
Publication statusPublished - 14 Dec 2015


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