Regular articleBeneficial effects of caffeine in a transgenic model of Alzheimer's disease-like tau pathology
Introduction
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by major memory impairments. Neuropathologically, AD is defined by the extracellular accumulation of amyloid beta (Aβ) peptides into amyloid plaques, and the presence of intraneuronal fibrillar aggregates of hyper- and abnormally-phosphorylated tau proteins (Masters et al., 1985, Sergeant et al., 2008). Tau pathology is observed early in the brain stem and entorhinal cortex (Braak et al., 2011) and its progression in the cortex from entorhinal cortex, then hippocampus, and finally neocortex corresponds to the progression of the symptoms in AD (Duyckaerts et al., 1997, Grober et al., 1999), supporting a pivotal role of tau pathology in AD-related memory impairments. Various genetic and environmental risk factors have been found to be associated with dementia and/or AD (for a review see Reitz et al., 2011) and several were found to impact tau. Notably, we and others demonstrated that environmental or lifestyle-related factors such as physical exercise (Belarbi et al., 2011), anesthetics (Le Freche et al., 2012, Whittington et al., 2013), or obesity/diabetes (Leboucher et al., 2013, Papon et al., 2013) modulate tau pathology and associated memory disturbances.
The methylxanthine caffeine (1,3,7-trimethylxanthine) is the world's most popular psychoactive drug. Longitudinal studies suggested a benefit of caffeine consumption toward age-related cognitive decline (Ritchie et al., 2007, Van Gelder et al., 2007). Other retrospective or prospective studies support that caffeine intake reduces AD risk (Eskelinen et al., 2009, Lindsay et al., 2002, Maia and de Mendonça, 2002). In line, higher plasma caffeine levels were found to be associated with a reduced risk of dementia or a delayed onset in patients with mild cognitive impairments (Cao et al., 2012). So far, the preclinical impact of caffeine in a pathophysiological context related to AD has been essentially evaluated in experimental models of amyloidogenesis. Notably, chronic caffeine intake through drinking water (0.3 g/L) was found to improve memory and mitigate amyloid burden in APPsw transgenic mice (Arendash et al., 2006, Arendash et al., 2009, see Blum et al., 2013 for review). Accordingly, caffeine was also found to improve the life span in Aβ-expressing worms (Lublin et al., 2011). Other studies indicated that low to moderate doses of caffeine are able to protect from Aβ-induced neuronal degeneration and memory impairments (Dall'Igna et al., 2003, Dall'Igna et al., 2007).
In sharp contrast, effects of caffeine have never been evaluated in a model of AD-like tau pathology. To address this question, we determined effects of chronic caffeine intake in the THY-Tau22 mouse model progressively developing hippocampal tau pathology and spatial memory defects (Burnouf et al., 2013, Leboucher et al., 2013, Schindowski et al., 2006).
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Animals and treatment
THY-Tau22 male mice (C57Bl6/J background) were generated by overexpression of human 4-repeat Tau mutated at sites G272V and P301S under the control of Thy1.2 promoter (Schindowski et al., 2006). The THY-Tau22 model is characterized by a major tau expression in the hippocampal formation, with limited pathology in the cortex and no significant pathology in the spinal cord making it a reliable model to evaluate modulators consequences on hippocampal tau pathology and its related impact on behavior
Mouse monitoring and caffeine concentrations
Animals were monitored all along the treatment, from 2- to 12- month-old. In our experimental conditions, we did neither encounter mortality nor signs of animal suffering in caffeine-treated animals. At completion of experiments, water-treated animals exhibited a body weight gain reaching 136.8% ± 2.6% of their initial body weight. Caffeine consumers exhibited a lower body weight gain reaching 127.9% ± 1.3% of initial body weight (p = 0.002 vs. water consumers), in line with previous
Discussion
The present data demonstrate that chronic caffeine intake reduces hippocampal tau hyperphosphorylation and the level of some tau fragments, mitigates neuroinflammation and prevents subsequent memory impairments in a transgenic mouse model of tauopathy.
Chronic delivery of caffeine at 0.3 g/L through drinking water was chosen according to previous data reporting significant benefit in a transgenic mouse model of amyloidogenesis (Arendash et al., 2006, Arendash et al., 2009). According to our
Disclosure statement
The authors report no actual or potential conflict of interest.
Acknowledgements
This work was supported by grants from France Alzheimer (to David Blum) and LECMA/Alzheimer Forschung Initiative (to David Blum and Christa E Müller). Our laboratory is also supported by the LabEx (excellence laboratory) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease), Inserm, CNRS, Université Lille 2, Région Nord/Pas-de-Calais, DN2M, ANR (ADORATAU), and FUI MEDIALZ. The authors thank the animal facility of IMPRT-IFR114 and M. Besegher, I.
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