Increased 4R-Tau Induces Pathological Changes in a Human-Tau Mouse Model
Open accessAbstract
Pathological evidence for selective four-repeat (4R) tau deposition in certain dementias and exon 10-positioned MAPT mutations together suggest a 4R-specific role in causing disease. However, direct assessments of 4R toxicity have not yet been accomplished in vivo. Increasing 4R-tau expression without change to total tau in human tau-expressing mice induced more severe seizures and nesting behavior abnormality, increased tau phosphorylation, and produced a shift toward oligomeric tau. Exon 10 skipping could also be accomplished in vivo, providing support for a 4R-tau targeted approach to target 4R-tau toxicity and, in cases of primary MAPT mutation, eliminate the disease-causing mutation.
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Increased 4R:3R tau ratios have been found to promote tau phosphorylation and oligomerization, and to induce behavioral abnormality in a mouse model expressing human tau.
“Increased 4R:3R tau ratios have been found to promote tau phosphorylation and oligomerization, and to induce behavioral abnormality in a mouse model expressing human tau [223].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [223]
Similar ASO mRNA-targeted approaches have improved disease phenotypes in rat models of SOD1-related ALS, mouse models of Huntington's disease and FTDP-17, and in C9ORF72 patient-derived cell lines.
“Similar ASO mRNA-targeted approaches have improved disease phenotypes in rat models of superoxide dismutase 1 (SOD1)-related ALS (17), mouse models of Huntington’s disease (18) and FTDP-17 (19), and in C9ORF72 patient-derived cell lines (20, 21).”
From Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy (2017) · cites this paper as [19]
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References 36 · Cited by 175
- Authors
- Schoch, K. M., DeVos, S. L., Miller, R. L., Chun, S. J., Norrbom, M., Wozniak, D. F., Dawson, H. N., Bennett, C. F., Rigo, F., & Miller, T. M.
- Affiliations
- Washington University in St. Louis (US)
- Ionis Pharmaceuticals (United States) (US)
- Duke Medical Center (US)
- Corresponding author
- Miller, Timothy M.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2016-06
- Volume
- 90
- Issue
- 5
- Pages
- 941-947
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC5040069
- OpenAlex
- W2406449858
- Cited by
- 175
- References
- 36
- Citations by year
- 2026: 12 · 2025: 14 · 2024: 10 · 2023: 16 · 2022: 14 · 2021: 19 · 2020: 25 · 2019: 28 · 2018: 20 · 2017: 15 · 2016: 2
- FWCI
- 17.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Washington University in St. Louis
- National Institute on Aging (R21AG044719, P50AG005681)
- National Institute of Neurological Disorders and Stroke (F32NS089225, P30NS057105, K08NS074194, R01NS078398)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- 4R tau, tauopathy, tau phosphorylation, tau oligomerization, seizures, nesting behavior, MAPT mutations, tau toxicity, Alzheimer's disease
- MeSH terms
- Animals, Brain, Exons, Humans, Models, Biological, Mutation, Nesting Behavior, Phosphorylation, RNA Splicing, Seizures, Solubility, Oligonucleotides, Antisense, tau Proteins, Trinucleotide Repeat Expansion, Protein Isoforms, Mice, Infusions, Intraventricular
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