Abstract
Altered autophagy contributes to the pathogenesis of Alzheimer’s disease and other tauopathies, for which curative treatment options are still lacking. We have recently shown that trehalose reduces tau pathology in a tauopathy mouse model by stimulation of autophagy. Here, we studied the effect of the autophagy inducing drug rapamycin on the progression of tau pathology in P301S mutant tau transgenic mice. Rapamycin treatment resulted in a significant reduction in cortical tau tangles, less tau hyperphosphorylation, and lowered levels of insoluble tau in the forebrain. The favourable effect of rapamycin on tau pathology was paralleled by a qualitative reduction in astrogliosis. These effects were visible with early preventive or late treatment. We further noted an accumulation of the autophagy associated proteins p62 and LC3 in aged tangle bearing P301S mice that was lowered upon rapamycin treatment. Thus, rapamycin treatment defers the progression of tau pathology in a tauopathy animal model and autophagy stimulation may constitute a therapeutic approach for patients suffering from tauopathies.
Highlights
Alzheimer’s disease (AD) and fronto-temporal dementia with tau inclusions (FTD-T) are the most frequent types of dementia [1]
While in vehicle treated mice, abundant Gallyas stain positive tangle pathology was seen throughout the cortex, pronounced in rostral motor cortex, only few isolated tangles formed in the cortex of rapamycin treated 5MT P301S mice (Fig. 1C)
We report a significant alleviation of cortical tau pathology in a murine tauopathy model following long- and short-term administration of the autophagy inducing drug rapamycin
Summary
Alzheimer’s disease (AD) and fronto-temporal dementia with tau inclusions (FTD-T) are the most frequent types of dementia [1]. They are characterized by intraneuronal accumulation, hyperphosphorylation and aggregation of tau protein. First studies investigating the use of rapamycin for the cure of neurodegenerative disorders in transgenic mouse models reported reduced neuronal protein aggregation following rapamycin administration in a murine model of Huntington’s disease [9], a triple transgenic model of Alzheimer’s disease [10,11], and recently in a model of spinocerebellar ataxia type 3 [12]
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