Inflammasome implication in neurodegenerative diseases. A role for inflammasome in Parkinson's disease?
Year: 2016
Type: dissertation
Abstract: Neuroinflammation is the local reaction of the brain to infection, trauma, toxic molecules or protein aggregates.The brain resident macrophages, microglia, are able to trigger an appropriate response involving secretion of cytokines and chemokines, resulting in the activation of astrocytes and recruitment of peripheral immune cells.The activated astrocytes also produce pro-inflammatory molecules that can lead to a vicious inflammatory circle in the brain.This toxic environment produced by both cell types seems to be one of the causes of neuronal death in neurodegenerative diseases.IL-1 plays an important role in this response; yet its expression and mode of action in the brain are not fully understood and its precise implication in neurodegenerative diseases needs further characterization.Therefore, the aim of this study was to obtain a better understanding of the role of the inflammasome-dependent IL-1 signalling within the brain as well as its possible implication in neurodegenerative diseases.The main objectives were i) to profile the expression and regulation of inflammasome in microglia and astrocytes, ii) to test the reactivity of inflammasome to compounds-related to neurodegenerative diseases iii) to investigate the implication of inflammasome in Parkinson's disease (PD).Our results indicate that the capacity to form a functional NLRP3 inflammasome and to secrete IL-1 is limited to the microglial compartment in the mouse brain.Indeed, we were not able to observe IL-1 secretion from astrocytes, nor do they express all NLRP3 inflammasome components.The capacity of these cells to express others inflammasome complexes also seems compromised, contrarily to microglia which exhibit the potentiality to express AIM2, NLRC4 or non-canonical inflammasome.In addition to IL-1, microglia were able to secrete IL-18, IL-1 and HMGB1 in an NLRP3 inflammasome-dependent way and through mechanisms similar to those observed in macrophages.Moreover, microglia stimulation with neurodegeneration-related compounds, such as amyloid-β peptide, rotenone or ATP resulted in the inflammasome activation and IL-1 release, suggesting that the microglial inflammasome can play a role in the neuroinflammation observed during neurodegenerative disease.Finally, if NLRP3 is linked to Alzheimer's pathogenesis, our preliminary results tend to indicate that genetic ablation of NLRP3 do not exert any significant impact on the neurodegenerative processes occurring in an in vivo model of Parkinson's disease.However, deeper investigations will be needed to better define the role of the inflammasome and its targets in PD.
Author: Audrey Gustin
Institution: University of Luxembourg
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2310099388