Abstract

Although tau pathology, behavioral deficits, and neuronal loss are observed in patients with tauopathies, the relationship between these endpoints has not been clearly established. Here we found that rTg4510 mice, which overexpress human mutant tau in the forebrain, develop progressive age-dependent increases in locomotor activity (LMA), which correlates with neurofibrillary tangle (NFT) pathology, hyperphosphorylated tau levels, and brain atrophy. To further clarify the relationship between these endpoints, we treated the rTg4510 mice with either doxycycline to reduce mutant tau expression or an O-GlcNAcase inhibitor Thiamet G, which has been shown to ameliorate tau pathology in animal models. We found that both doxycycline and Thiamet G treatments starting at 2 months of age prevented the progression of hyperactivity, slowed brain atrophy, and reduced brain hyperphosphorylated tau. In contrast, initiating doxycycline treatment at 4 months reduced neither brain hyperphosphorylated tau nor hyperactivity, further confirming the relationship between these measures. Collectively, our results demonstrate a unique behavioral phenotype in the rTg4510 mouse model of tauopathy that strongly correlates with disease progression, and that early interventions which reduce tau pathology ameliorate the progression of the locomotor dysfunction. These findings suggest that better understanding the relationship between locomotor deficits and tau pathology in the rTg4510 model may improve our understanding of the mechanisms underlying behavioral disturbances in patients with tauopathies.

Highlights

  • Intracellular accumulation of neurofibrillary tangles (NFTs) is the hallmark of a family of neurodegenerative diseases known as tauopathies, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), corticobasal degeneration (CBD), Pick’s disease, and progressive supranuclear palsy (PSP)

  • Locomotor function was evaluated by measuring the spontaneous locomotor activity (LMA) of rTg4510 mice and age-matched wild type (WT) littermates in an open-field box

  • To better understand the tau pathology in hyperactive rTg4510 mice, we examined the relationship between LMA and NFT counts in entorhinal cortex using nitrated tau (Tau-nY29) antibody immunostaining, which preferentially labels fibrillar tau lesions [30]

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Summary

Introduction

Intracellular accumulation of neurofibrillary tangles (NFTs) is the hallmark of a family of neurodegenerative diseases known as tauopathies, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), corticobasal degeneration (CBD), Pick’s disease, and progressive supranuclear palsy (PSP). AD is the most common tauopathy, and the amount of NFTs correlates with the severity of cognitive dysfunction [1,2]. Most tau mutations affect tau microtubule binding or result in alternative splicing of tau mRNA [4]. The discovery of specific tau mutations has facilitated the generation of mouse models of tauopathy, which has allowed for pre-clinical evaluation of novel therapeutic strategies to treat these diseases [5]

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