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Preventive methylene blue treatment preserves cognition in mice expressing full-length pro-aggregant human Tau.

ABSTRACT: Neurofibrillary tangles (NFT) composed of Tau are hallmarks of neurodegeneration in Alzheimer disease. Transgenic mice expressing full-length pro-aggregant human Tau (2N4R Tau-?K280, termed Tau(?K)) or its repeat domain (TauRD-?K280, TauRD(?K)) develop a progressive Tau pathology with missorting, phosphorylation, aggregation of Tau, loss of synapses and functional deficits. Whereas TauRD(?K) assembles into NFT concomitant with neuronal death, Tau(?K) 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.Preventive and therapeutic MB application failed to avert or recover learning and memory deficits of TauRD(?K) mice. Similarly, therapeutic MB treatment initiated after onset of cognitive impairments was ineffective in Tau(?K) mice. In contrast, preventive MB application starting before onset of functional deficits preserved cognition of Tau(?K) mice. Beside improved learning and memory, MB-treated Tau(?K) 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.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.

SUBMITTER: Hochgrafe K

PROVIDER: S-EPMC4425867 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Preventive methylene blue treatment preserves cognition in mice expressing full-length pro-aggregant human Tau.

Hochgräfe Katja K Sydow Astrid A Matenia Dorthe D Cadinu Daniela D Könen Stefanie S Petrova Olga O Pickhardt Marcus M Goll Petra P Morellini Fabio F Mandelkow Eckhard E Mandelkow Eva-Maria EM

Acta neuropathologica communications 20150510

<h4>Introduction</h4>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 Tau(ΔK)) or its repeat domain (TauRD-ΔK280, TauRD(ΔK)) develop a progressive Tau pathology with missorting, phosphorylation, aggregation of Tau, loss of synapses and functional deficits. Whereas TauRD(ΔK) assembles into NFT concomitant with neuronal death, Tau(ΔK) accumulates into Tau pre ...[more]

PMID: 25958115

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Project description:BACKGROUND:Alzheimer's disease is associated with the accumulation of intracellular Tau tangles within neurons and extracellular amyloid-? plaques in the brain parenchyma, which altogether results in synaptic loss and neurodegeneration. Extracellular concentrations of oligomers and aggregated proteins initiate microglial activation and convert their state of synaptic surveillance into a destructive inflammatory state. Although Tau oligomers have fleeting nature, they were shown to mediate neurotoxicity and microglial pro-inflammation. Due to the instability of oligomers, in vitro experiments become challenging, and hence, the stability of the full-length Tau oligomers is a major concern. METHODS:In this study, we have prepared and stabilized hTau40WT oligomers, which were purified by size-exclusion chromatography. The formation of the oligomers was confirmed by western blot, thioflavin-S, 8-anilinonaphthaalene-1-sulfonic acid fluorescence, and circular dichroism spectroscopy, which determine the intermolecular cross-? sheet structure and hydrophobicity. The efficiency of N9 microglial cells to phagocytose hTau40WT oligomer and subsequent microglial activation was studied by immunofluorescence microscopy with apotome. The one-way ANOVA was performed for the statistical analysis of fluorometric assay and microscopic analysis. RESULTS:Full-length Tau oligomers were detected in heterogeneous globular structures ranging from 5 to 50?nm as observed by high-resolution transmission electron microscopy, which was further characterized by oligomer-specific A11 antibody. Immunocytochemistry studies for oligomer treatment were evidenced with A11+ Iba1high microglia, suggesting that the phagocytosis of extracellular Tau oligomers leads to microglial activation. Also, the microglia were observed with remodeled filopodia-like actin structures upon the exposure of oligomers and aggregated Tau. CONCLUSION:The peri-membrane polymerization of actin filament and co-localization of Iba1 relate to the microglial movements for phagocytosis. Here, these findings suggest that microglia modified actin cytoskeleton for phagocytosis and rapid clearance of Tau oligomers in Alzheimer's disease condition.

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Preventive methylene blue treatment preserves cognition in mice expressing full-length pro-aggregant human Tau.

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Preventive methylene blue treatment preserves cognition in mice expressing full-length pro-aggregant human Tau.

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