Abstract
BackgroundMAPT 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.
Highlights
Microtubule associated protein tau (MAPT) mutations cause neurodegenerative diseases such as frontotemporal dementia but, strikingly, patients with the same mutation may have different clinical phenotypes
Given that phenotypic variation occurs in patients carrying the same P301L mutation [1, 14,15,16], we extrapolated that the TgTauP301L line might be manifesting a related biological effect and, might allow us to understand parameters that dictate phenotypic diversity [17]
The “call rate” for scoring polymorphisms on the array was between 98.2% and 99.7% (Additional file 1: Table S1) with the positions of the residual unscored single nucleotide polymorphisms (SNPs) not being shared by the three inbred derivatives
Summary
MAPT mutations cause neurodegenerative diseases such as frontotemporal dementia but, strikingly, patients with the same mutation may have different clinical phenotypes. Major questions in neurodegenerative disease research include the origins of sporadic disease, the time-lag before germline mutations in central nervous system (CNS)-expressed genes produce neurological symptoms and the degree of impact of prion-like effects upon CNS dysfunction. All of these issues are germane to diagnostic and therapeutic strategies and all occur in the literature of diseases involving the Tau protein. While primary Tauopathies include corticobasal degeneration and progressive supranuclear palsy, cases with germline mutations in the Tau gene (MAPT) are notable These were originally detected in the context of a clinical syndrome referred to as FTDP-17 (Frontotemporal Dementia with Parkinsonism linked to chromosome 17) [1]. The term “Tauopathy” has been used as a descriptor for any neurologic syndrome that feature abnormal forms of this protein; for example, Alzheimer’s disease (AD) can be considered a secondary Tauopathy where neurofibrillary tangles (NFTs) containing hyperphosphorylated forms of Tau are a hallmark feature, yet where MAPT is free of mutations that alter protein structure or spliced forms
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