Seeding of Normal Tau by Pathological Tau Conformers Drives Pathogenesis of Alzheimer-like Tangles
Open accessAbstract
Neurofibrillary tangles (NFTs) in Alzheimer disease and related tauopathies are composed of insoluble hyperphosphorylated Tau protein, but the mechanisms underlying the conversion of highly soluble Tau into insoluble NFTs remain elusive. Here, we demonstrate that introduction of minute quantities of misfolded preformed Tau fibrils (Tau pffs) into Tau-expressing cells rapidly recruit large amounts of soluble Tau into filamentous inclusions resembling NFTs with unprecedented efficiency, suggesting a "seeding"-recruitment process as a highly plausible mechanism underlying NFT formation in vivo. Consistent with the emerging concept of prion-like transmissibility of disease-causing amyloidogenic proteins, we found that spontaneous uptake of Tau pffs into cells is likely mediated by endocytosis, suggesting a potential mechanism for the propagation of Tau lesions in tauopathy brains. Furthermore, sequestration of soluble Tau by pff-induced Tau aggregates attenuates microtubule overstabilization in Tau-expressing cells, supporting the hypothesis of a Tau loss-of-function toxicity in cells harboring NFTs. In summary, our study establishes a cellular system that robustly develops authentic NFT-like Tau aggregates, which provides mechanistic insights into NFT pathogenesis and a potential tool for identifying Tau-based therapeutics.
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The current clinical trial literature is compatible with the idea that AβP-related substances kindle a self-propagating process related to neocortical NFTs.
“The current clinical trial literature is compatible with the idea that AβP-related substances kindle a self-propagating process related to neocortical NFTs, as has been hypothesized (266-269).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [269]
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“In vitro, aggregates of tau, a-synuclein, polyglutamine, and SOD1 all can be taken up by endocytosis and induce the misfolding of the corresponding intracellular proteins; moreover, cytoplasmic protein aggregates can translocate from one cultured cell to another.(64,66,80,81,83,84,86,88) The mode of cell-to-cell trans…”
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- Authors
- Guo, J. L., & Lee, V. M.-Y.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- Lee, Virginia M.-Y.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-04
- Volume
- 286
- Issue
- 17
- Pages
- 15317-15331
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3083182
- OpenAlex
- W2005755021
- Cited by
- 636
- References
- 67
- Citations by year
- 2026: 26 · 2025: 33 · 2024: 26 · 2023: 41 · 2022: 36 · 2021: 48 · 2020: 55 · 2019: 46 · 2018: 39 · 2017: 37 · 2016: 41 · 2015: 49 · 2014: 45 · 2013: 60 · 2012: 36
- FWCI
- 34.89
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AG 17586)
- National Institute on Aging (P01AG017586, AG17586)
- 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
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tau protein, neurofibrillary tangles, Alzheimer's disease, tauopathy, preformed fibrils, seeding, protein misfolding, endocytosis, microtubule stabilization, tau aggregation, prion-like propagation
- MeSH terms
- Alzheimer Disease, Cell Line, Humans, Solubility, Neurofibrillary Tangles, tau Proteins, Tauopathies, Amyloidogenic Proteins
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