Reducing tau aggregates with anle138b delays disease progression in a mouse model of tauopathies

Jens A Wagner ,Wolfgang Zinth,Jochen H Weishaupt,Alexander Kleinknecht,Daniel Weckbecker,Martin Fuhrmann,Stefan Remy,Bettina Göricke,Andrei Leonov,Dan Ehninger,Sergey Ryazanov,Carolin Miklitz,Anne M Reiner,Hans A Kretzschmar,Julia Steffen,Christian Griesinger,Armin Giese,Song Shi,Chengjie Xiong ,Sybille Krauß

doi:10.1007/s00401-015-1483-3

Abstract

Pathological tau aggregation leads to filamentous tau inclusions and characterizes neurodegenerative tauopathies such as Alzheimer’s disease and frontotemporal dementia and parkinsonism linked to chromosome 17. Tau aggregation coincides with clinical symptoms and is thought to mediate neurodegeneration. Transgenic mice overexpressing mutant human P301S tau exhibit many neuropathological features of human tauopathies including behavioral deficits and increased mortality. Here, we show that the di-phenyl-pyrazole anle138b binds to aggregated tau and inhibits tau aggregation in vitro and in vivo. Furthermore, anle138b treatment effectively ameliorates disease symptoms, increases survival time and improves cognition of tau transgenic PS19 mice. In addition, we found decreased synapse and neuron loss accompanied by a decreased gliosis in the hippocampus. Our results suggest that reducing tau aggregates with anle138b may represent an effective and promising approach for the treatment of human tauopathies.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-015-1483-3) contains supplementary material, which is available to authorized users.

Highlights

The conversion of soluble tau monomers into insoluble fibrils is a key component in the pathogenesis of neurodegenerative tauopathies, including Alzheimer’s disease, frontotemporal dementia and parkinsonism linked to chromosome 17, Pick’s disease, progressive supranuclear palsy, and corticobasal degeneration [30, 44]
In a cell free in vitro tau aggregation assay with subsequent scanning for intensely fluorescent targets (SIFT) analysis [8], we examined the effect of anle138b on tau aggregation (Fig. 1b)
We found that anle138b inhibits the formation of pathological tau aggregates in vitro and in vivo and thereby improves cognition, neuropathology and survival in a mouse model of tauopathies

Summary

Introduction

The conversion of soluble tau monomers into insoluble fibrils is a key component in the pathogenesis of neurodegenerative tauopathies, including Alzheimer’s disease, frontotemporal dementia and parkinsonism linked to chromosome 17, Pick’s disease, progressive supranuclear palsy, and corticobasal degeneration [30, 44]. In Alzheimer’s disease, tau pathology correlates with neuronal loss and clinical symptoms [2, 10, 18]. Accumulation of aggregated tau is associated with memory deficits and neurodegeneration [6, 40, 41]. Inhibiting the aggregation of tau with small molecules reduced neurotoxicity in vitro [29]. Together, these observations suggest that aggregated tau is not merely a neuropathological marker; tau aggregation rather represents a main target of a diseasemodifying therapy for tauopathies. Despite the identification of tau aggregation inhibitors in vitro [4, 13, 38, 39, 48], only methylene blue was tested in a tau transgenic mouse model and

Methods

Results

Conclusion