Caffeine and adenosine A2A receptor inactivation decrease striatal neuropathology in a lentiviral-based model of Machado–Joseph disease
Article first published online: 26 APR 2013
Copyright © 2013 American Neurological Association
Annals of Neurology
Volume 73, Issue 5, pages 655–666, May 2013
How to Cite
Gonçalves, N., Simões, A. T., Cunha, R. A. and de Almeida, L. P. (2013), Caffeine and adenosine A2A receptor inactivation decrease striatal neuropathology in a lentiviral-based model of Machado–Joseph disease. Ann Neurol., 73: 655–666. doi: 10.1002/ana.23866
- Issue published online: 28 MAY 2013
- Article first published online: 26 APR 2013
- Accepted manuscript online: 11 FEB 2013 04:44AM EST
- Manuscript Accepted: 1 FEB 2013
- Manuscript Revised: 21 JAN 2013
- Manuscript Received: 11 JUN 2012
- Fundação para a Ciência e a Tecnologia (FCT) . Grant Numbers: SAU-FCF/70384/2006 , SAU-NEU/099307/2008 , SAU-NEU/108668/2008
- Richard Chin and Lily Lock Machado Joseph Disease Research Fund
- Association Française Contre les Myopathies
- Defense Advanced Research Projects Agency (R.A.C.)
- National Ataxia Foundation (N.G., A.T.S., L.P.d.A.)
- FCT fellowships . Grant Numbers: BD/33186/2007 , BD/38636/2007
Machado–Joseph disease (MJD) is a neurodegenerative disorder associated with an abnormal CAG expansion, which translates into an expanded polyglutamine tract within ataxin-3. There is no therapy to prevent or modify disease progression. Because caffeine (a nonselective adenosine receptor antagonist) and selective adenosine A2A receptor (A2AR) blockade alleviate neurodegeneration in different brain diseases, namely at early stages of another polyglutamine-related disorder such as Huntington's disease, we now tested their ability to control MJD-associated neurodegeneration.
MJD was modeled by transducing the striatum of male adult C57Bl/6 mice with lentiviral vectors encoding mutant ataxin-3 in one hemisphere and wild-type ataxin-3 in the other hemisphere (as internal control). Caffeine (1g/L) was applied through the drinking water. Mice were killed at different time points (from 2 to 12 weeks) to probe for the appearance of different morphological changes using immunohistochemical analysis.
Mutant ataxin-3 caused an evolving neuronal dysfunction (loss of DARPP-32 staining) leading to neurodegeneration (cresyl violet and neuronal nuclei staining) associated with increased number of mutant ataxin-3 inclusions in the basal ganglia. Notably, mutant ataxin-3 triggered early synaptotoxicity (decreased synaptophysin and microtubule-associated protein-2 staining) and reactive gliosis (glial fibrillary acidic protein and CD11b staining), which predated neuronal dysfunction and damage. Caffeine reduced the appearance of all these morphological modifications, which were also abrogated in mice with a global A2AR inactivation (knockout).
Our findings provide a demonstration that synaptotoxicity and gliosis are precocious events in MJD and that caffeine and A2AR inactivation decrease MJD-associated striatal pathology, which paves the way to consider A2ARs as novel therapeutic targets to manage MJD. Ann Neurol 2013;73:655–666