Cited by 636Alzheimer's disease research and treatmentsPrion Diseases and Protein MisfoldingDementia and Cognitive Impairment Research

Seeding of Normal Tau by Pathological Tau Conformers Drives Pathogenesis of Alzheimer-like Tangles

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Guo, Jing L., Lee, Virginia M.-Y.·2011·Journal of Biological Chemistry

Abstract

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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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)
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
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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