Caspase signalling controls microglia activation and neurotoxicity

Miguel A. Burguillos, Tomas Deierborg, Edel Kavanagh, Annette Persson, Nabil Hajji, Albert Garcia-Quintanilla, Josefina Cano, Patrik Brundin, Elisabet Englund, Jose L. Venero () and Bertrand Joseph ()
Additional contact information
Miguel A. Burguillos: Cancer Centrum Karolinska, Karolinska Institutet
Tomas Deierborg: Neuronal Survival Unit, Wallenberg Neuroscience Center
Edel Kavanagh: Cancer Centrum Karolinska, Karolinska Institutet
Annette Persson: Lund University Hospital
Nabil Hajji: Cancer Centrum Karolinska, Karolinska Institutet
Albert Garcia-Quintanilla: Servicio de Biología, Centro de Investigación, Tecnología e Innovación, Universidad de Sevilla (CITIUS)
Josefina Cano: Facultad de Farmacia, Universidad de Sevilla, and Instituto de Biomedicina de Sevilla
Patrik Brundin: Neuronal Survival Unit, Wallenberg Neuroscience Center
Elisabet Englund: Lund University Hospital
Jose L. Venero: Facultad de Farmacia, Universidad de Sevilla, and Instituto de Biomedicina de Sevilla
Bertrand Joseph: Cancer Centrum Karolinska, Karolinska Institutet

Nature, 2011, vol. 472, issue 7343, 319-324

Abstract: Abstract Activation of microglia and inflammation-mediated neurotoxicity are suggested to play a decisive role in the pathogenesis of several neurodegenerative disorders. Activated microglia release pro-inflammatory factors that may be neurotoxic. Here we show that the orderly activation of caspase-8 and caspase-3/7, known executioners of apoptotic cell death, regulate microglia activation through a protein kinase C (PKC)-δ-dependent pathway. We find that stimulation of microglia with various inflammogens activates caspase-8 and caspase-3/7 in microglia without triggering cell death in vitro and in vivo. Knockdown or chemical inhibition of each of these caspases hindered microglia activation and consequently reduced neurotoxicity. We observe that these caspases are activated in microglia in the ventral mesencephalon of Parkinson’s disease (PD) and the frontal cortex of individuals with Alzheimer’s disease (AD). Taken together, we show that caspase-8 and caspase-3/7 are involved in regulating microglia activation. We conclude that inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves.

Date: 2011
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DOI: 10.1038/nature09788

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