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Cited by 362Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Tau filaments from multiple cases of sporadic and inherited Alzheimer's disease adopt a common fold

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Falcon, Benjamin, Zhang, Wenjuan, Schweighauser, Manuel, Murzin, Alexey G., Vidal, Ruben, Garringer, Holly J., Ghetti, Bernardino, Scheres, Sjors H. W. +1 more·2018·Acta Neuropathologica
DOI 10.1007/s00401-018-1914-zPMC PMC6208733

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Abstract

The ordered assembly of tau protein into abnormal filaments is a defining characteristic of Alzheimer's disease (AD) and other neurodegenerative disorders. It is not known if the structures of tau filaments vary within, or between, the brains of individuals with AD. We used a combination of electron cryo-microscopy (cryo-EM) and immuno-gold negative-stain electron microscopy (immuno-EM) to determine the structures of paired helical filaments (PHFs) and straight filaments (SFs) from the frontal cortex of 17 cases of AD (15 sporadic and 2 inherited) and 2 cases of atypical AD (posterior cortical atrophy). The high-resolution structures of PHFs and SFs from the frontal cortex of 3 cases of AD, 2 sporadic and 1 inherited, were determined by cryo-EM. We also used immuno-EM to study the PHFs and SFs from a number of cortical and subcortical brain regions. PHFs outnumbered SFs in all AD cases. By cryo-EM, PHFs and SFs were made of two C-shaped protofilaments with a combined cross-β/β-helix structure, as described previously for one case of AD. The higher resolution structures obtained here showed two additional amino acids at each end of the protofilament. The immuno-EM findings, which indicated the presence of repeats 3 and 4, but not of the N-terminal regions of repeats 1 and 2, of tau in the filament cores of all AD cases, were consistent with the cryo-EM results. These findings show that there is no significant variation in tau filament structures between individuals with AD. This knowledge will be crucial for understanding the mechanisms that underlie tau filament formation and for developing novel diagnostics and therapies.

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  • Filaments from AD tissue are characterized by a single conformer.

    “While filaments from AD tissue are characterized by a single conformer (72)”

    From MAP2 caps tau fibrils and inhibits aggregation (2023) · cites this paper as [72]

    The Discussion reports a common C-shaped protofilament fold across the AD cases studied. But the Introduction describes paired helical and straight filaments as ultrastructural polymorphs with different inter-protofilament packing, so a single conformer of whole AD filaments overstates the finding. No page numbers are available in our copy. (LLM, conf=0.84)

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References 47 · Cited by 362

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Authors
Falcon, B., Zhang, W., Schweighauser, M., Murzin, A. G., Vidal, R., Garringer, H. J., Ghetti, B., Scheres, S. H. W., & Goedert, M.
Affiliations
  • MRC Laboratory of Molecular Biology (GB)
  • Indiana University Indianapolis (US)
Corresponding author
  • Scheres, Sjors H. W.
  • Goedert, Michel
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2018-10-01
Volume
136
Issue
5
Pages
699-708
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-018-1914-z
PMC
PMC6208733
OpenAlex
W2891796239
Cited by
362
References
47
Citations by year
2026: 32 · 2025: 36 · 2024: 59 · 2023: 49 · 2022: 50 · 2021: 51 · 2020: 49 · 2019: 34 · 2018: 2
FWCI
23.38
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • PMC
  • Apollo (cc-by)
Funders
  • Medical Research Council (MC_UP_A025_1013, MC_U105184291)
  • EU Joint Programme – Neurodegenerative Disease Research
  • Innovative Medicines Initiative
  • Eli Lilly and Company
  • National Institutes of Health (P30-AG010133)
  • Alzheimer's Association (Zenith Award)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
tau protein, tau filaments, Alzheimer's disease, paired helical filaments, straight filaments, protofilaments, cross-β structure, sporadic Alzheimer's disease, posterior cortical atrophy, frontal cortex
MeSH terms
Exome Sequencing, Aged, Aged, 80 and over, Alzheimer Disease, Apolipoproteins E, Brain, Female, Humans, Male, Middle Aged, Models, Anatomic, Mutation, Microscopy, Immunoelectron, Amyloid beta-Protein Precursor, Neurofibrillary Tangles, tau Proteins, Cryoelectron Microscopy

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