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Caspase signalling controls microglia activation and neurotoxicity
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Journal Article
Caspase signalling controls microglia activation and neurotoxicity
2011
Overview
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.
Caspases and neurotoxicity
Brain inflammation is a typical feature of neurodegenerative diseases and acute forms of brain injury. Microglia are thought to play a part in the pathogenesis of such disorders by secreting neurotoxic cytokines. Experiments in cell and animal models of inflammation show that microglia activation requires the orderly activation of caspase-8 and caspase-3/7 — well known as agents of cell death. Inhibition of the caspase cascade prevents activation of microglia and protects against neurotoxicity. Caspase activation also occurs in microglia in the brains of patients with Parkinson's disease and Alzheimer's disease, raising the prospect that caspase inhibitors may have therapeutic potential.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 692/420
/ Adult and adolescent clinical studies
/ Alzheimer Disease - enzymology
/ Alzheimer Disease - pathology
/ Animals
/ Biological and medical sciences
/ Caspases
/ Cellular signal transduction
/ Humanities and Social Sciences
/ Humans
/ Lipopolysaccharides - pharmacology
/ Medicinska och farmaceutiska grundvetenskaper
/ Mice
/ Neurotoxicity Syndromes - enzymology
/ Neurotoxicity Syndromes - metabolism
/ Neurotoxicity Syndromes - pathology
/ Organic mental disorders. Neuropsychology
/ Parkinson Disease - enzymology
/ Parkinson Disease - pathology
/ Protein Kinase C-delta - chemistry
/ Protein Kinase C-delta - metabolism
/ Proteins
/ Psychology. Psychoanalysis. Psychiatry
/ Rats
/ Rodents
/ Science
/ Substantia Nigra - enzymology
