期刊
EMBO JOURNAL
卷 34, 期 24, 页码 3028-3041出版社
WILEY
DOI: 10.15252/embj.201592748
关键词
Alzheimer's disease; neurodegeneration; neurofibrillary tangles; P301L tau; prion-like
资金
- German Research Association (DFG)
- Alzheimer's Research UK
- Chief Scientist's Office, Scotland
- NIH [NS41997, AG 26249]
- Massachusetts General Hospital
- Alzheimers Research UK [ARUK-SPG2013-1, ART-TRF2011-2] Funding Source: researchfish
- Alzheimer's Society [195] Funding Source: researchfish
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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