Inhibition of tau aggregation in a novel Caenorhabditis elegans model of tauopathy mitigates proteotoxicity.

Institute of Biology III, University of Freiburg, 79104 Freiburg, Germany.
Human Molecular Genetics (Impact Factor: 6.68). 05/2012; 21(16):3587-603. DOI: 10.1093/hmg/dds190
Source: PubMed

ABSTRACT Increased Tau protein amyloidogenicity has been causatively implicated in several neurodegenerative diseases, collectively called tauopathies. In pathological conditions, Tau becomes hyperphosphorylated and forms intracellular aggregates. The deletion of K280, which is a mutation that commonly appears in patients with frontotemporal dementia with Parkinsonism linked to chromosome 17, enhances Tau aggregation propensity (pro-aggregation). In contrast, introduction of the I277P and I308P mutations prevents β-sheet formation and subsequent aggregation (anti-aggregation). In this study, we created a tauopathy model by expressing pro- or anti-aggregant Tau species in the nervous system of Caenorhabditis elegans. Animals expressing the highly amyloidogenic Tau species showed accelerated Tau aggregation and pathology manifested by severely impaired motility and evident neuronal dysfunction. In addition, we observed that the axonal transport of mitochondria was perturbed in these animals. Control animals expressing the anti-aggregant combination had rather mild phenotype. We subsequently tested several Tau aggregation inhibitor compounds and observed a mitigation of Tau proteotoxicity. In particular, a novel compound that crosses the blood-brain barrier of mammals proved effective in ameliorating the motility as well as delaying the accumulation of neuronal defects. Our study establishes a new C. elegans model of Tau aggregation-mediated toxicity and supports the emerging notion that inhibiting the nucleation of Tau aggregation can be neuroprotective.

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    ABSTRACT: Introduction Neurofibrillary tangles (NFT) composed of Tau are hallmarks of neurodegeneration in Alzheimer disease. Transgenic mice expressing full-length pro-aggregant human Tau (2N4R Tau-ΔK280, termed TauΔK) or its repeat domain (TauRD-ΔK280, TauRDΔK) develop a progressive Tau pathology with missorting, phosphorylation, aggregation of Tau, loss of synapses and functional deficits. Whereas TauRDΔK assembles into NFT concomitant with neuronal death, TauΔK accumulates into Tau pretangles without overt neuronal loss. Both forms cause a comparable cognitive decline (with onset at 10mo and 12mo, respectively), which is rescued upon switch-off of transgene expression. Since methylene blue (MB) is able to inhibit Tau aggregation in vitro, we investigated whether MB can prevent or rescue Tau-induced cognitive impairments in our mouse models. Both types of mice received MB orally using different preventive and therapeutic treatment protocols, initiated either before or after disease onset. The cognitive status of the mice was assessed by behavior tasks (open field, Morris water maze) to determine the most successful conditions for therapeutic intervention. Results Preventive and therapeutic MB application failed to avert or recover learning and memory deficits of TauRDΔK mice. Similarly, therapeutic MB treatment initiated after onset of cognitive impairments was ineffective in TauΔK mice. In contrast, preventive MB application starting before onset of functional deficits preserved cognition of TauΔK mice. Beside improved learning and memory, MB-treated TauΔK mice showed a strong decrease of insoluble Tau, a reduction of conformationally changed (MC1) and phosphorylated Tau species (AT180, PHF1) as well as an upregulation of protein degradation systems (autophagy and proteasome). This argues for additional pleiotropic effects of MB beyond its properties as Tau aggregation inhibitor. Conclusions Our data support the use of Tau aggregation inhibitors as potential drugs for the treatment of AD and other tauopathies and highlights the need for preventive treatment before onset of cognitive impairments. Electronic supplementary material The online version of this article (doi:10.1186/s40478-015-0204-4) contains supplementary material, which is available to authorized users.
    05/2015; 3(1). DOI:10.1186/s40478-015-0204-4
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    ABSTRACT: Our aims are to review animal models of tauopathies, which include a number of brain disorders with various aetiologies, including aging, genetics, infectious diseases, toxins, trauma, and other unknown factors. Tauopathies are characterised by the accumulation of filaments of the microtubule-associated tau protein. The different aetiopathogeneses and distinct molecular events involved in tau aggregation have led to the development of various animal models for these diseases. In this review, rather than listing all current models, we focus on specific animal models addressing, among others, the question of tau hyperphosphorylation, tau aggregation and tau spreading. Physiological conditions, including normal aging and hibernation, may exhibit tau phosphorylation and some aspects of tauopathies. However, most of the models of tauopathies involve genetically modified animals (mostly rodents, but also fruit fly, zebrafish, and worm). Some of these models have been crucial for the development of therapeutic approaches in humans. The present review shows the difficulty in pinpointing a specific mechanism that may be targeted in tauopathies but also opens up new avenues for innovative therapeutic strategies. This article is protected by copyright. All rights reserved.
    Neuropathology and Applied Neurobiology 11/2014; 41(1). DOI:10.1111/nan.12200 · 4.97 Impact Factor
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    ABSTRACT: The disheartening results of recent clinical trials for neurodegenerative disease (ND) therapeutics underscore the need for a more comprehensive understanding of the underlying disease biology before effective therapies can be devised. One hallmark of many NDs is a disruption in protein homeostasis. Therefore, investigating the role of protein homeostasis in these diseases is central to delineating their underlying pathobiology. Here, we review the seminal role that chemical biology has played in furthering the research on and treatment of dysfunctional protein homeostasis in NDs. We also discuss the vital and predictive role of model systems in identifying conserved homeostasis pathways and genes therein that are altered in neurodegeneration. Integrating approaches from chemical biology with the use of model systems yields a powerful toolkit with which to unravel the complexities of ND biology.
    Nature Chemical Biology 11/2014; 10(11):911-920. DOI:10.1038/nchembio.1663 · 13.22 Impact Factor


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