Proteopathic tau seeding predicts tauopathy in vivo
Open accessAbstract
Significance: Prion-like propagation of proteopathic seeds may underlie the progression of neurodegenerative diseases, including the tauopathies and synucleinopathies. We aimed to construct a versatile and simple cell assay to sensitively and specifically detect proteopathic seeding activity. Using a combination of FRET flow cytometry and a tau monoclonal FRET biosensor cell line, we report seed detection in the femtomolar range. This assay is easily applied to human brain homogenates and selectively responds to Alzheimer's disease but not Huntington's disease brains. By comparing seeding activity in a mouse model of human tauopathy, we demonstrate detection of proteopathic seeding far in advance of standard histopathological markers. Proteopathic seeding is thus an early marker of tauopathy, consistent with a causal role for tau seeds in neurodegeneration.
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The seeding assay was performed using TauRD P301S FRET Biosensor Cells.
“The seeding assay was performed using TauRD P301S FRET Biosensor Cells (Holmes et al., 2014).”
From Network analysis identifies strain-dependent response to tau and tau seeding-associated genes (2023) · cites this paper as Holmes et al., 2014
Tau propagates pathology among neurons.
“Several lines of evidence indicate tau propagates pathology among neurons.”
From Spontaneous pathology in PS19 tauopathy mice progresses via brain networks (2025) · cites this paper as Holmes et al., 2014
Tau assemblies enter cells to trigger intracellular aggregation.
“Tau assemblies enter cells to trigger intracellular aggregation (Frost et al., 2009; Holmes et al., 2014)”
From Spontaneous pathology in PS19 tauopathy mice progresses via brain networks (2025) · cites this paper as Holmes et al., 2014
Human tau expression was consistently present across brain sections spanning the rostrocaudal extent of the hippocampus at 3, 6, 9 and 12 months of age in PS19 mice.
“Staining for human tau (with HJ8.5 antibody (Yanamandra et al., 2013, Holmes et al., 2014)) showed consistent expression of human tau across brain sections spanning the rostrocaudal extent of the hippocampus at 3, 6, 9 and 12 months of age (Fig. 3).”
From Spontaneous pathology in PS19 tauopathy mice progresses via brain networks (2025) · cites this paper as Holmes et al., 2014
Cluster C1 contained five 6mo brains and a 9mo brain.
“The cluster with lowest overall p-tau intensity (Fig. 5A, “C1”) contained five 6mo brains, when consistent pathology emerges in the PS19 model (Yoshiyama et al., 2007; Holmes et al., 2014), as well as a 9mo brain.”
From Spontaneous pathology in PS19 tauopathy mice progresses via brain networks (2025) · cites this paper as Holmes et al., 2014
Tau aggregates have prion-like seeding and spreading properties.
“In addition, tau aggregates have been shown to have prion-like seeding and spreading properties [40].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [40]
A FRET-based biosensor assay using recombinant repeat domain tau revealed tau seeding activity in PS19 mice as early as 1.5-2 months of age.
“it has revealed tau seeding activity in PS19 mice as early as 1.5–2 months of age [66].”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [66]
LMW and sarkosyl-soluble Tau fractions do not show positive seeding activity in biosensor assays.
“These Tau fractions do not have positive seeding activity in biosensor assays (Holmes et al., 2014; Takeda et al., 2015).”
From Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease (2020) · cites this paper as Holmes et al., 2014
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Traumatic Brain Injury Induces Tau Aggregation and Spreading
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Experimental evidence for the age dependence of tau protein spread in the brain
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Seeding selectivity and ultrasensitive detection of tau aggregate conformers of Alzheimer disease
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Removing endogenous tau does not prevent tau propagation yet reduces its neurotoxicity
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Cofactors are essential constituents of stable and seeding-active tau fibrils
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Trem2 deletion enhances tau dispersion and pathology through microglia exosomes
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Microglial priming in Alzheimer’s disease
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Tau reduction in the presence of amyloid-β prevents tau pathology and neuronal death in vivo
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PICALM and Alzheimer’s Disease: An Update and Perspectives
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Targeting tau: clinical trials and novel therapeutic approaches
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α-Synuclein Oligomers Induce a Unique Toxic Tau Strain
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AAV-mediated expression of anti-tau scFvs decreases tau accumulation in a mouse model of tauopathy
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Self-citationRegional vulnerability and spreading of hyperphosphorylated tau in seeded mouse brain
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RT-QuIC detection of tauopathies using full-length tau substrates
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“Moreover, isolated AD-tau was transfected into tau RD P301S fluorescence resonance energy transfer (FRET) biosensor cells and demonstrated strong seeding activity (Figure 1C) in the quantification of the integrated FRET density via flow cytometry [22].”
MethodExploiting the intrinsic misfolding propensity of the KRAS oncoprotein
Janssen, K., Claes, F., Van de Velde, D., Wehbi, V. L., Houben, B., Lampi, Y., Nys, M., Khodaparast, L., Khodaparast, L., Louros, N., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2214921120 · Cited by 10 · see citing works
Spontaneous pathology in PS19 tauopathy mice progresses via brain networks
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Self-citationDetection and quantitative analysis of dynamic GPCRs interactions using flow cytometry-based FRET
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Network analysis identifies strain-dependent response to tau and tau seeding-associated genes
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“The seeding assay was performed using TauRD P301S FRET Biosensor Cells (Holmes et al., 2014).”
Anti-tau antibodies targeting a conformation-dependent epitope selectively bind seeds
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Self-citation
- Authors
- Holmes, B. B., Furman, J. L., Mahan, T. E., Yamasaki, T. R., Mirbaha, H., Eades, W. C., Belaygorod, L., Cairns, N. J., Holtzman, D. M., & Diamond, M. I.
- Affiliations
- Hope Center for Neurological Disorders (US)
- Washington University in St. Louis (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-09-26
- Volume
- 111
- Issue
- 41
- Pages
- E4376-85
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4205609
- OpenAlex
- W1966312717
- Cited by
- 696
- References
- 58
- Citations by year
- 2026: 60 · 2025: 96 · 2024: 63 · 2023: 71 · 2022: 63 · 2021: 82 · 2020: 68 · 2019: 52 · 2018: 52 · 2017: 34 · 2016: 26 · 2015: 24 · 2014: 3
- FWCI
- 19.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P 50 AG05681, P50AG005681, P01AG003991)
- National Cancer Institute (P30CA091842)
- National Institute of Neurological Disorders and Stroke (F32NS087805, F31NS079039, P30NS057105, NS057105, R01NS071835)
- National Center for Research Resources (S10-RR0227552)
- 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 seeding, tauopathy, Alzheimer's disease, Huntington's disease, prion-like propagation, FRET biosensor, synuclein, early biomarkers, neurodegeneration, tau fibrils
- MeSH terms
- Aging, Alzheimer Disease, Animals, Cells, Cultured, Disease Models, Animal, Flow Cytometry, Humans, Mice, Transgenic, Protein Binding, Biosensing Techniques, Biomarkers, tau Proteins, Tauopathies, Fluorescence Resonance Energy Transfer, Mutant Proteins, HEK293 Cells, Protein Aggregation, Pathological
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