Removing endogenous tau does not prevent tau propagation yet reduces its neurotoxicity
Open accessAbstract
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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Trans-synaptic tau propagation and aggregation can be independent of endogenous soluble tau, but the absence of endogenous tau reduces its neurotoxicity.
“In addition, trans-synaptic tau propagation and aggregation can also be independent of the presence of endogenous soluble tau, but the absence of endogenous tau reduces its neurotoxicity [63].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [63]
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- Authors
- Wegmann, S., Maury, E. A., Kirk, M. J., Saqran, L., Roe, A., DeVos, S. L., Nicholls, S., Fan, Z., Takeda, S., Cagsal‐Getkin, O., William, C. M., Spires‐Jones, T. L., Pitstick, R., Carlson, G. A., Pooler, A. M., & Hyman, B. T.
- Affiliations
- Harvard University (US)
- Euan MacDonald Centre for Motor Neuron Disease Research (GB)
- McLaughlin Research Institute (US)
- Corresponding author
- Hyman, Bradley T
- ORCID
- Venue
- The EMBO Journal
- Published
- 2015-11-04
- Volume
- 34
- Issue
- 24
- Pages
- 3028-3041
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC4687785
- OpenAlex
- W1940013884
- Cited by
- 132
- References
- 55
- Citations by year
- 2026: 9 · 2025: 10 · 2024: 11 · 2023: 10 · 2022: 12 · 2021: 16 · 2020: 8 · 2019: 12 · 2018: 13 · 2017: 14 · 2016: 15 · 2015: 1 · 2014: 1
- FWCI
- 10.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (publishedVersion, other-oa)
- Funders
- Massachusetts General Hospital
- NIH (AG 26249, NS41997)
- German Research Association
- Alzheimer's Research UK
- Chief Scientist's Office, Scotland
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau protein, tau propagation, prion-like mechanisms, neurofibrillary tangles, P301L tau, tau knockout mice, neurotoxicity, Alzheimer's disease, tauopathy, entorhinal cortex, dentate gyrus, neurodegeneration
- MeSH terms
- Alzheimer Disease, Animals, Cells, Cultured, Mice, Inbred C57BL, Neurons, tau Proteins, Entorhinal Cortex, Mutation, Missense, Mice
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