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Cited by 213Alzheimer's disease research and treatmentsPrion Diseases and Protein MisfoldingAmyotrophic Lateral Sclerosis Research

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Propagation of Tau aggregates

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Goedert, Michel, Spillantini, Maria Grazia·2017·Molecular Brain
DOI 10.1186/s13041-017-0298-7PMC PMC5450399
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Abstract

Since 2009, evidence has accumulated to suggest that Tau aggregates form first in a small number of brain cells, from where they propagate to other regions, resulting in neurodegeneration and disease. Propagation of Tau aggregates is often called prion-like, which refers to the capacity of an assembled protein to induce the same abnormal conformation in a protein of the same kind, initiating a self-amplifying cascade. In addition, prion-like encompasses the release of protein aggregates from brain cells and their uptake by neighbouring cells. In mice, the intracerebral injection of Tau inclusions induced the ordered assembly of monomeric Tau, followed by its spreading to distant brain regions. Short fibrils constituted the major species of seed-competent Tau. The existence of several human Tauopathies with distinct fibril morphologies has led to the suggestion that different molecular conformers (or strains) of aggregated Tau exist.

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Figures

Fig. 1 Human brain Tau isoforms and MAPT mutations. a MAPT and the six Tau isoforms expressed in adult human brain. MAPT consists of 16 exons (E). Alternative mRNA splicing of E2 (red), E3 (green), and E10 (yellow) gives rise to six tau isoforms (amino acids 352–441). Constitutively spliced exons (E1, E4, E5, E7, E9, E11, E12, E13) are shown in blue. E0, which is part of the promoter, and E14 are noncoding (white). E6 and E8 (violet) are not transcribed in human brain. E4a (orange) is only expressed in the peripheral nervous system. The repeats (R1-R4) are shown, with three isoforms having four repeats each (4R) and three isoforms having three repeats each (3R). Each repeat is 31 amino acids in length. Exons and introns are not drawn to scale. b Mutations in MAPT in cases of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17 T); 49 coding region mutations and 10 intronic mutations flanking E10 are shown
Fig. 1 Human brain Tau isoforms and MAPT mutations. a MAPT and the six Tau isoforms expressed in adult human brain. MAPT consists of 16 exons (E). Alternative mRNA splicing of E2 (red), E3 (green), and E10 (yellow) gives rise to six tau isoforms (amino acids 352–441). Constitutively spliced exons (E1, E4, E5, E7, E9, E11, E12, E13) are shown in blue. E0, which is part of the promoter, and E14 are noncoding (white). E6 and E8 (violet) are not transcribed in human brain. E4a (orange) is only expressed in the peripheral nervous system. The repeats (R1-R4) are shown, with three isoforms having four repeats each (4R) and three isoforms having three repeats each (3R). Each repeat is 31 amino acids in length. Exons and introns are not drawn to scale. b Mutations in MAPT in cases of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17 T); 49 coding region mutations and 10 intronic mutations flanking E10 are shownCC BY · PubMed Central
Fig. 2 Induction of filamentous Tau pathology in mice transgenic for wild-type human Tau (line ALZ17) following injection with brain extracts from symptomatic mice transgenic for human mutant P301S tau. Staining of the hippocampal CA3 region of 18-month-old ALZ17 mice with anti-Tau antibodies AT8 and AT100 and Gallyas-Braak silver. Non-injected (left), 15 months after injection of brain extract from non-transgenic control mice (middle) and 15 months after injection with brain extract from 6-month-old mice transgenic for human P301S Tau (right). The sections were counterstained with haematoxylin. Scale bar = 50 μm
Fig. 2 Induction of filamentous Tau pathology in mice transgenic for wild-type human Tau (line ALZ17) following injection with brain extracts from symptomatic mice transgenic for human mutant P301S tau. Staining of the hippocampal CA3 region of 18-month-old ALZ17 mice with anti-Tau antibodies AT8 and AT100 and Gallyas-Braak silver. Non-injected (left), 15 months after injection of brain extract from non-transgenic control mice (middle) and 15 months after injection with brain extract from 6-month-old mice transgenic for human P301S Tau (right). The sections were counterstained with haematoxylin. Scale bar = 50 μmCC BY · PubMed Central
Fig. 3 Seeding of Tau aggregation with sucrose gradient fractions from the brains of mice transgenic for human mutant P301S Tau in a cell-based assay. The mice were aged 4.4 weeks (no symptoms, no Tau filaments) or 24.4 weeks (symptoms, abundant Tau filaments). Sucrose gradient fractions were used to seed aggregation of Tau in HEK cells expressing 1N4R Tau with the P301S mutation. The pellet from a 100,000 g spin of seeded cells was analysed by Western blotting for total Tau and Tau phosphorylated at S202/T205 (anti-Tau antibodies DA9 and AT8). Filamentous Tau runs at approximately 68 kDa (HMW, high-molecular weight); non-filamentous Tau runs at approximately 59 kDa (LMW, low-molecular weight). The positive control consisted in seeding with sarkosyl-extracted Tau from unfractionated brains of symptomatic transgenic P301S Tau mice and the normalised positive control was seeding with sarkosyl-extracted Tau from symptomatic mice, normalised for total Tau levels relative to those of the sucrose gradient fractions. Seeding ability correlated with the presence of the 64 kDa band in 24.4-week-old mice (20–50% sucrose gradient fractions). No seeding was observed upon addition of sucrose gradient fractions from the brains of 4.4-week-old mice
Fig. 3 Seeding of Tau aggregation with sucrose gradient fractions from the brains of mice transgenic for human mutant P301S Tau in a cell-based assay. The mice were aged 4.4 weeks (no symptoms, no Tau filaments) or 24.4 weeks (symptoms, abundant Tau filaments). Sucrose gradient fractions were used to seed aggregation of Tau in HEK cells expressing 1N4R Tau with the P301S mutation. The pellet from a 100,000 g spin of seeded cells was analysed by Western blotting for total Tau and Tau phosphorylated at S202/T205 (anti-Tau antibodies DA9 and AT8). Filamentous Tau runs at approximately 68 kDa (HMW, high-molecular weight); non-filamentous Tau runs at approximately 59 kDa (LMW, low-molecular weight). The positive control consisted in seeding with sarkosyl-extracted Tau from unfractionated brains of symptomatic transgenic P301S Tau mice and the normalised positive control was seeding with sarkosyl-extracted Tau from symptomatic mice, normalised for total Tau levels relative to those of the sucrose gradient fractions. Seeding ability correlated with the presence of the 64 kDa band in 24.4-week-old mice (20–50% sucrose gradient fractions). No seeding was observed upon addition of sucrose gradient fractions from the brains of 4.4-week-old miceCC BY · PubMed Central

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Metadata

Authors
Goedert, M., & Spillantini, M. G.
Affiliations
  • MRC Laboratory of Molecular Biology (GB)
  • University of Cambridge (GB)
Corresponding author
Goedert, Michel
ORCID
Venue
Molecular Brain
Publisher
Springer Science and Business Media LLC
Published
2017-05-30
Volume
10
Issue
1
Pages
18-18
ISSN
1756-6606 (ISSN-L)
DOI
10.1186/s13041-017-0298-7
PMC
PMC5450399
OpenAlex
W2617946428
Cited by
213
References
84
Citations by year
2026: 15 · 2025: 17 · 2024: 16 · 2023: 13 · 2022: 24 · 2021: 27 · 2020: 25 · 2019: 42 · 2018: 25 · 2017: 9
FWCI
3.39
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Molecular Brain (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Apollo (University of Cambridge) (submittedVersion, cc-by)
  • Apollo
Funders
National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC/C013102/1)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
  • Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
tau aggregates, prion-like propagation, tauopathy, neurodegeneration, fibril morphology, intracerebral injection
MeSH terms
Animals, Humans, tau Proteins, Protein Isoforms, Protein Aggregates

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