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The CNS in inbred transgenic models of 4-repeat Tauopathy develops consistent tau seeding capacity yet focal and diverse patterns of protein deposition

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Eskandari-Sedighi, Ghazaleh, Daude, Nathalie, Gapeshina, Hristina, Sanders, David W., Kamali-Jamil, Razieh, Yang, Jing, Shi, Beipei, Wille, Holger +4 more·2017·Molecular Neurodegeneration
DOI 10.1186/s13024-017-0215-7PMC PMC5628424
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Abstract

BACKGROUND: MAPT mutations cause neurodegenerative diseases such as frontotemporal dementia but, strikingly, patients with the same mutation may have different clinical phenotypes. METHODS: Given heterogeneities observed in a transgenic (Tg) mouse line expressing low levels of human (2 N, 4R) P301L Tau, we backcrossed founder stocks of mice to C57BL/6Tac, 129/SvEvTac and FVB/NJ inbred backgrounds to discern the role of genetic versus environmental effects on disease-related phenotypes. RESULTS: founder line had similar quality and steady-state quantity of Tau production, accumulation of abnormally phosphorylated 64-68 kDa Tau species from 90 days of age onwards and neuronal loss in aged Tg mice. Variegation was not seen in the pattern of transgene expression and seeding properties in a fluorescence-based cellular assay indicated a single "strain" of misfolded Tau. However, in other regards, the aged Tg mice were heterogeneous; there was incomplete penetrance for Tau deposition despite maintained transgene expression in aged animals and, for animals with Tau deposits, distinctions were noted even within each subline. Three classes of rostral deposition in the cortex, hippocampus and striatum accounted for 75% of pathology-positive mice yet the mean ages of mice scored as class I, II or III were not significantly different and, hence, did not fit with a predictable progression from one class to another defined by chronological age. Two other patterns of Tau deposition designated as classes IV and V, occurred in caudal structures. Other pathology-positive Tg mice of similar age not falling within classes I-V presented with focal accumulations in additional caudal neuroanatomical areas including the locus coeruleus. Electron microscopy revealed that brains of Classes I, II and IV animals all exhibit straight filaments, but with coiled filaments and occasional twisted filaments apparent in Class I. Most strikingly, Class I, II and IV animals presented with distinct western blot signatures after trypsin digestion of sarkosyl-insoluble Tau. CONCLUSIONS: Qualitative variations in the neuroanatomy of Tau deposition in genetically constrained slow models of primary Tauopathy establish that non-synchronous, focal events contribute to the pathogenic process. Phenotypic diversity in these models suggests a potential parallel to the phenotypic variation seen in P301L patients.

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  • Previously, genetic background has been shown to influence the amount of tau and the presence of at least one phospho-epitope in tau transgenic models.

    “Previously, genetic background has been shown to influence the amount of tau and the presence of at least one phospho-epitope in tau transgenic models (Eskandari-Sedighi et al., 2017; Yanagisawa et al., 2021; Bailey et al., 2014).”

    From Network analysis identifies strain-dependent response to tau and tau seeding-associated genes (2023) · cites this paper as Eskandari-Sedighi et al., 2017

    The Results section, “Genetic profiles and tau expression in sublines of TgTauP301L mice” (page unavailable), reports no significant difference in human tau expression between the three genetic backgrounds. The Background says variation in tau deposition was shared between, and independent of, those backgrounds; the Results also report AT8-negative animals in all three. This paper therefore does not show the attributed genetic-background effect on tau amount or phospho-epitope presence. (LLM, conf=0.86)

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Authors
Eskandari-Sedighi, G., Daude, N., Gapeshina, H., Sanders, D. W., Kamali-Jamil, R., Yang, J., Shi, B., Wille, H., Ghetti, B., Diamond, M. I., Janus, C., & Westaway, D.
Affiliations
  • University of Alberta (CA)
  • The University of Texas Southwestern Medical Center (US)
  • Indiana University Indianapolis (US)
  • University of Florida (US)
Corresponding author
Westaway, David
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2017-10-04
Volume
12
Issue
1
Pages
72-72
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-017-0215-7
PMC
PMC5628424
OpenAlex
W2763708652
Cited by
22
References
13
Citations by year
2026: 1 · 2025: 2 · 2024: 1 · 2023: 2 · 2022: 4 · 2021: 5 · 2020: 6 · 2019: 1
FWCI
1.42
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Canada Research Chairs (Tier 1)
  • CIHR (CA) (PS148962)
  • Alberta Innovates (ABIBS AEP 201600021 and 20160023)
  • Faculty of Graduate Studies and Research, University of Alberta (President's International Doctoral Award)
  • Alberta Innovates Bio Solutions (AI 201700005)
  • the Alzheimer Society of Alberta and Northwest Territories
  • Canada Foundation for Innovation (CA)
  • Faculty of Medicine and Dentistry 75th anniversary award
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
tauopathy, P301L tau, MAPT mutations, transgenic mouse model, tau seeding, tau phosphorylation, locus coeruleus, frontotemporal dementia, phenotypic heterogeneity, neurofibrillary tangles, trypsin digestion, sarkosyl-insoluble tau, neuronal loss
MeSH terms
Animals, Brain, Disease Models, Animal, Humans, Mice, Inbred C57BL, Mice, Transgenic, Phenotype, tau Proteins, Tauopathies, Mice

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