P1‐003: MICROGLIA ACTIVATION COMPROMISES NEURONAL AUTOPHAGY THROUGH A NLRP3 INFLAMMASOME‐MEDIATED MECHANISM

The role of autophagy in CNS disorders is not well understood but there is evidence that disruption of this house keeping system could led to neurodegeneration. Involvement of NLRP3 in pathology of the APP/PS1 mouse model has been recently demonstrated. Aggregation of autophagy proteins likes LC3 and p62 and inflammatory markers including IL-1ß have been found in neurodegenrative diseases. However, the relationship between inflammation and autophagy remains unclear Primary wild type and NLRP3 ko microglia and murine BV2 cells were exposed to different inflammatory stimuli including Lipopolysaccharides (LPS), amyloid peptide (Aß42) and adenosine triphosphate (ATP) for specific time periods and their conditional medium was collected. Primary neurons and N2a cells were exposed to supernatant derived from immunostimulated microglia in order to assess autophagy markers. Autophagy markers were gradually changed in a time dependent manner and nicely regulated by the severity of the conditional stress.Exposure to supernatants from immunostimulated microglia compromised neuronal autophagy and increased p62 in vitro and in vivo. Interstingly, microglial NLRP3 inflammasome ko prevented the inhibition of neuronal autophagy. Our findings indicate that a NLRP3 inflammasome dependent and microglial derived stimulus affects neuronal autophagy and led to intracellular protein accumulations in neurons. This may represent a novel mechanism by which microglia driven neuroinflammation affects neuronal functioning.