Involvement of exosomes in inflammatory dopaminergic neurodegeneration.

Abstract

Parkinson's disease is one of the neurodegenerative disorders, caused by progressive degeneration of dopamine (DA) neurons in substantia nigra. Microglial activation by IFNγ/LPS treatment triggers selective loss of DA neurons in midbrain slice cultures. Exosomes are regarded as a novel factor that mediates cell-to-cell interactions. In the present study, we investigated the involvement of exosomes in DA neurodegeneration triggered by microglial activation in rat midbrain slice culture. IFNγ/LPS treatment prominently elevated exosome release from midbrain slice cultures. GW4869, a neutral sphingomyelinase 2 inhibitor, decreased exosome release and prevented IFNγ/LPS-triggered DA degeneration without the inhibition of microglial activation. To directly elucidate the involvement of activated microglial-derived exosome in DA neurodegeneration, we isolated exosomes from culture media of IFNγ/LPS-treated slices and treated them to other slice cultures. Although exosomes from control slices did not affect the survival of DA neurons, exosomes from IFNγ/LPS-treated slices significantly decreased DA neurons. Microglial activation was not triggered by exosomes from IFNγ/LPS-treated slices. These findings suggest that exosomes from activated microglia directly react to neurons and mediate DA neurodegeneration.