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

Ghazaleh Eskandari-Sedighi, Nathalie Daude, Hristina Gapeshina, David W. Sanders, Razieh Kamali-Jamil, Jing Yang, Beipei Shi, Holger Wille, Bernardino Ghetti, Marc I. Diamond, Christopher Janus, David Westaway

Research output: Contribution to journalArticle

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: Three inbred derivatives of a TgTauP301L 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.

Original languageEnglish (US)
Article number72
JournalMolecular Neurodegeneration
Volume12
Issue number1
DOIs
StatePublished - Oct 4 2017

Fingerprint

Tauopathies
Transgenic Mice
Transgenes
Proteins
Pathology
Phenotype
Neuroanatomy
Frontotemporal Dementia
Mutation
Locus Coeruleus
Penetrance
Inbred C57BL Mouse
Neurodegenerative Diseases
Trypsin
Digestion
Hippocampus
Electron Microscopy
Fluorescence
Western Blotting
Brain

Keywords

  • Aging
  • Focal pathology
  • Neuronal loss
  • P301L mutation
  • Stochastic events
  • Transgenic mouse

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

The CNS in inbred transgenic models of 4-repeat Tauopathy develops consistent tau seeding capacity yet focal and diverse patterns of protein deposition. / Eskandari-Sedighi, Ghazaleh; Daude, Nathalie; Gapeshina, Hristina; Sanders, David W.; Kamali-Jamil, Razieh; Yang, Jing; Shi, Beipei; Wille, Holger; Ghetti, Bernardino; Diamond, Marc I.; Janus, Christopher; Westaway, David.

In: Molecular Neurodegeneration, Vol. 12, No. 1, 72, 04.10.2017.

Research output: Contribution to journalArticle

Eskandari-Sedighi, G, Daude, N, Gapeshina, H, Sanders, DW, Kamali-Jamil, R, Yang, J, Shi, B, Wille, H, Ghetti, B, Diamond, MI, Janus, C & Westaway, D 2017, 'The CNS in inbred transgenic models of 4-repeat Tauopathy develops consistent tau seeding capacity yet focal and diverse patterns of protein deposition', Molecular Neurodegeneration, vol. 12, no. 1, 72. https://doi.org/10.1186/s13024-017-0215-7
Eskandari-Sedighi, Ghazaleh ; Daude, Nathalie ; Gapeshina, Hristina ; Sanders, David W. ; Kamali-Jamil, Razieh ; Yang, Jing ; Shi, Beipei ; Wille, Holger ; Ghetti, Bernardino ; Diamond, Marc I. ; Janus, Christopher ; Westaway, David. / The CNS in inbred transgenic models of 4-repeat Tauopathy develops consistent tau seeding capacity yet focal and diverse patterns of protein deposition. In: Molecular Neurodegeneration. 2017 ; Vol. 12, No. 1.
@article{24d0e6ebfb474bc9a884b1ae73248b1e,
title = "The CNS in inbred transgenic models of 4-repeat Tauopathy develops consistent tau seeding capacity yet focal and diverse patterns of protein deposition",
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: Three inbred derivatives of a TgTauP301L 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.",
keywords = "Aging, Focal pathology, Neuronal loss, P301L mutation, Stochastic events, Transgenic mouse",
author = "Ghazaleh Eskandari-Sedighi and Nathalie Daude and Hristina Gapeshina and Sanders, {David W.} and Razieh Kamali-Jamil and Jing Yang and Beipei Shi and Holger Wille and Bernardino Ghetti and Diamond, {Marc I.} and Christopher Janus and David Westaway",
year = "2017",
month = "10",
day = "4",
doi = "10.1186/s13024-017-0215-7",
language = "English (US)",
volume = "12",
journal = "Molecular Neurodegeneration",
issn = "1750-1326",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - The CNS in inbred transgenic models of 4-repeat Tauopathy develops consistent tau seeding capacity yet focal and diverse patterns of protein deposition

AU - Eskandari-Sedighi, Ghazaleh

AU - Daude, Nathalie

AU - Gapeshina, Hristina

AU - Sanders, David W.

AU - Kamali-Jamil, Razieh

AU - Yang, Jing

AU - Shi, Beipei

AU - Wille, Holger

AU - Ghetti, Bernardino

AU - Diamond, Marc I.

AU - Janus, Christopher

AU - Westaway, David

PY - 2017/10/4

Y1 - 2017/10/4

N2 - 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: Three inbred derivatives of a TgTauP301L 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.

AB - 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: Three inbred derivatives of a TgTauP301L 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.

KW - Aging

KW - Focal pathology

KW - Neuronal loss

KW - P301L mutation

KW - Stochastic events

KW - Transgenic mouse

UR - http://www.scopus.com/inward/record.url?scp=85030461618&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85030461618&partnerID=8YFLogxK

U2 - 10.1186/s13024-017-0215-7

DO - 10.1186/s13024-017-0215-7

M3 - Article

C2 - 28978354

AN - SCOPUS:85030461618

VL - 12

JO - Molecular Neurodegeneration

JF - Molecular Neurodegeneration

SN - 1750-1326

IS - 1

M1 - 72

ER -