Molecular characterization of the minimal protease resistant tau unit of the Alzheimer's disease paired helical filament
Open accessAbstract
The Alzheimer's disease paired helical filament (PHF), after digestion with Pronase, retains its characteristic morphological features. We term this the protease resistant core PHF. A 12 kDa tau fragment can be released from the core as an essentially pure preparation. Sequence analysis of this fragment revealed six distinct N-termini beginning in the repeat region of tau. The precise C-terminus is unknown, but the fragment is approximately 100 residues long. A monoclonal antibody, mAb 423, which recognizes the core PHF and the 12 kDa tau fragment, does not recognize normal full-length tau. We describe cDNA synthesis and expression of candidate 12 kDa tau analogues which permit the mapping of the mAb 423 epitope. mAb 423 recognizes all and only those analogues which terminate at Glu391, which lies beyond the homology repeat region. Addition or removal of a single residue at the C-terminus abolishes immunoreactivity. Therefore, mAb 423, together with knowledge of the N-terminus, can be used to measure the precise extent of 12 kDa PHF core tau fragment which we term the minimal protease resistant tau unit of the core PHF. This unit is 93-95 residues long, which is equivalent to three repeats, but is 14-16 residues out of phase with respect to the maximum homology organization of the repeat region. mAb 423 labels isolated PHFs prior to Pronase digestion and intracellular granular and neurofibrillary degeneration in Alzheimer's disease tissues. The constraints which determine endogenous truncation at Glu391 appear to be characteristic of an assembled configuration of tau, either within the PHF or its precursor.
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The repeat region is a major contributor to the core structure of tau fibrils.
“The repeat region is a major contributor to the core structure of tau fibrils (14, 15).”
From MAP2 caps tau fibrils and inhibits aggregation (2023) · cites this paper as [14]
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- Authors
- Novak, M., Kabat, J., & Wischik, C. M.
- Affiliations
- MRC Laboratory of Molecular Biology (GB)
- Venue
- The EMBO Journal
- Published
- 1993-01-01
- Volume
- 12
- Issue
- 1
- Pages
- 365-370
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC413214
- OpenAlex
- W2158118162
- Cited by
- 398
- References
- 1
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 14 · 2023: 11 · 2022: 14 · 2021: 20 · 2020: 15 · 2019: 16 · 2018: 13 · 2017: 8 · 2016: 12 · 2015: 19 · 2014: 17 · 2013: 14 · 2012: 15
- FWCI
- 6.22
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Lister Institute of Preventive Medicine
- Medical Research Council
- 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, Alzheimer's disease, epitope mapping, C-terminal truncation, neurofibrillary degeneration, cDNA expression, pronase digestion
- MeSH terms
- Alzheimer Disease, Amino Acid Sequence, Antibodies, Monoclonal, Epitopes, Base Sequence, DNA, Electrophoresis, Polyacrylamide Gel, Hippocampus, Humans, Molecular Sequence Data, Oligodeoxyribonucleotides, Peptide Fragments, Endopeptidases, Pronase, Repetitive Sequences, Nucleic Acid, RNA, Messenger, Temporal Lobe, Immunoblotting, Polymerase Chain Reaction, tau Proteins, Sequence Homology, Amino Acid
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