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01.12.2017 | Research article | Ausgabe 1/2017 Open Access

Molecular Neurodegeneration 1/2017

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 > Ausgabe 1/2017
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
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s13024-017-0215-7) contains supplementary material, which is available to authorized users.



MAPT mutations cause neurodegenerative diseases such as frontotemporal dementia but, strikingly, patients with the same mutation may have different clinical phenotypes.


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.


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.


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.
Additional file 3: Figures S2-S5. Class I mice. These figures represent the counterparts of Fig. 4. stained with MC1, CP27, RZ3 and PHF1 antibodies, respectively. (ZIP 2909 kb)
Additional file 4: Figures S6-S9. Class II mice. These figures represent the counterparts of Fig. 5. stained with MC1, CP27, RZ3 and PHF1 antibodies, respectively. (ZIP 3613 kb)
Additional file 5: Figures S10-S13. Class III mice. These figures represent the counterparts of Fig. 6. stained with MC1, CP27, RZ3 and PHF1 antibodies, respectively. (ZIP 3238 kb)
Additional file 6: Figures S14-S17. Class IV mice. These figures represent the counterparts of Fig. 7. stained with MC1, CP27, RZ3 and PHF1 antibodies, respectively. (ZIP 2280 kb)
Additional file 7: Figure S18. Class V mice. This figure represents a counterpart of Fig. 8 stained with CP27, RZ3 and PHF1 antibodies. (TIFF 690 kb)
Additional file 8: Figure S19. Pathology in aged Tg mice assessed for insoluble Tau species. These data represent the counterparts (other hemi-brains) of the animals assessed for insoluble Tau species in Fig. 12; pathology class and genetic background are annotated. Scale bars for low power views = 2.5 mm, high power views = 50 μm. (TIFF 741 kb)
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