Proteomic Analysis of Hydromethylthionine in the Line 66 Model of Frontotemporal Dementia Demonstrates Actions on Tau-Dependent and Tau-Independent Networks.

Karima Schwab,Valeria Melis,Mandy Magbagbeolu,Gernot Riedel,Claude M Wischik,Charles R Harrington,Franz Theuring

doi:10.3390/cells10082162

Abstract

Abnormal aggregation of tau is the pathological hallmark of tauopathies including frontotemporal dementia (FTD). We have generated tau-transgenic mice that express the aggregation-prone P301S human tau (line 66). These mice present with early-onset, high tau load in brain and FTD-like behavioural deficiencies. Several of these behavioural phenotypes and tau pathology are reversed by treatment with hydromethylthionine but key pathways underlying these corrections remain elusive. In two proteomic experiments, line 66 mice were compared with wild-type mice and then vehicle and hydromethylthionine treatments of line 66 mice were compared. The brain proteome was investigated using two-dimensional electrophoresis and mass spectrometry to identify protein networks and pathways that were altered due to tau overexpression or modified by hydromethylthionine treatment. Overexpression of mutant tau induced metabolic/mitochondrial dysfunction, changes in synaptic transmission and in stress responses, and these functions were recovered by hydromethylthionine. Other pathways, such as NRF2, oxidative phosphorylation and protein ubiquitination were activated by hydromethylthionine, presumably independent of its function as a tau aggregation inhibitor. Our results suggest that hydromethylthionine recovers cellular activity in both a tau-dependent and a tau-independent fashion that could lead to a wide-spread improvement of homeostatic function in the FTD brain.

Highlights

Tauopathies, such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD), are distinct neurodegenerative disorders with overlapping pathology
The methylthioninium (MT) moiety can exist in oxidised (MT+ ) and reduced (LMT) forms and we have reported recently that LMTM blocks tau aggregation and propagation in vitro [46], reverses behavioural deficits and tau pathology in mice [47] and hydromethylthionine has pharmacological activity on brain structure and function in both AD [48] and FTD [49]
We report proteomic analysis of line 66 (L66) mice treated with two dosing regimes of LMTM, an approach that has not been available in other experimental models or in humans

Summary

Introduction

Tauopathies, such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD), are distinct neurodegenerative disorders with overlapping pathology. A common feature is the deposition of abnormal tau aggregates [1,2,3] which, under physiological conditions promotes microtubule assembly, stabilises axons and allows axonal branching and axonal transport [4]. Small oligomeric aggregates of tau are formed initially, with subsequent accumulation of tau in paired helical filaments (PHFs) and these changes contribute to synaptic dysfunction, microtubule collapse and neuronal death [6]. While several mutations in the longest human CNS tau isoform (htau40) appear to promote tau aggregation and have been associated with early onset frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) [7,8,9,10], relatively little is known about how these mutations affect the global proteome.

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