[Caspase inhibitors versus Parkinson's & Alzheimer's] (hat tip to Dew Diligence)
>>Nature. 2011 Mar 9. [Epub ahead of print]
Caspase signalling controls microglia activation and neurotoxicity.
Burguillos MA, Deierborg T, Kavanagh E, Persson A, Hajji N, Garcia-Quintanilla A, Cano J, Brundin P, Englund E, Venero JL, Joseph B.
1] Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, 171 76, Stockholm, Sweden [2] Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad de Sevilla, and Instituto de Biomedicina de Sevilla, 41012 Sevilla, Spain [3] Neuronal Survival Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, 221 84 Lund, Sweden.
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)-d-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.<<
Cheers, Tuck |
