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.MethodsGiven 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.ResultsThree 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.ConclusionsQualitative 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.Electronic supplementary materialThe online version of this article (10.1186/s13024-017-0215-7) contains supplementary material, which is available to authorized users.

Diverse, evolving conformer populations drive distinct phenotypes in frontotemporal lobar degeneration caused by the same MAPT-P301L mutation

“…Next, concentrations of sarkosyl-soluble tau in mouse hemi-brain samples divided along a sagittal axis and profiled by CDI were similar across all three genetic backgrounds ( Fig. 3a), compatible with prior blot analyses [29]. The ~ twofold higher levels than in non-transgenic controls reflect the differential affinity of capture antibody toward mice and human tau.…”

“…Cohorts of congenic derivatives of a TgTau P301L mouse line totaling 243 animals were profiled for tau deposition with the AT8 antibody as used for Braak staging of neurofibrillary pathology in human material [8] (Supplementary Table 1). The finding that several categories of pathological deposition of tau were represented in both sexes in Tg mouse stocks maintained in independent C57BL/6Tac, 129SvEv/Tac and FVB/NJ inbred sublines extends and underscores earlier analyses and argues against genomic variation in driving this diversity [29]. Concerning chronology, we considered whether different classes of neuroanatomical distribution of tau merely reflected pathological stages in a predictable progression.…”

“…TgTau P301L mice and their non-Tg littermates were derived by injections into oocytes from 129/SvEvTac x FVB/NJ F 1 mice and then bred further to obtain congenic and incipient congenic derivatives as described previously [29,69]. Animals were maintained in ventilated racks (Tecniplast) and fed irradiated chow (LabDiets, 5053…”

“…Electron micrographs were recorded with an Eagle 4 k × 4 k CCD camera (FEI Company). Morphologies of individual tau filaments were classified into "straight filaments", "coiled filaments", and "twisted ribbon-like filaments" as described previously [29].…”

“…While the extent to which data from tauopathy models and in vitro-generated tau aggregates fulfill these criteria is vigorously debated, we have explored these concepts to arrive at an understanding of the heterogeneity present within FTLD-MAPT. For this purpose we have used congenic lines of transgenic (Tg) mice expressing low levels of a P301L mutant version of the 2N4R spliced form of human tau [29,69] (Fig. 1a, b).…”