PATHOGENIC ROLE OF MICROGLIA-DERIVED MICROVESICLES IN NEURODEGENERATION

The characteristic feature of Alzheimer’s disease (AD) is the presence of extracellular amyloid-beta (Abeta) plaques, which are surrounded by activated microglial cells. Microglial cells during the long course of the disease can induce neuroinflammation and drive neurodegeneration. Recent evidence indicates that neuroinflammation negatively co-relates with cognitive state in AD. Furthermore it’s well accepted now that soluble pre-fibrillar Abeta species, rather than insoluble fibrils, are the most toxic forms of Abeta. This hypothesis is supported by the fact that plaque load reaches plateau before the clinical onset of AD. We investigated whether membrane microvesicles (MVs) released extracellularly by reactive microglia may contribute to AD degeneration. We found that production of myeloid MVs is strikingly high in AD patients and in subjects with mild cognitive impairment, and that AD MVs are toxic for cultured neurons. We demonstrated the mechanism responsible for MV neurotoxicity in vitro, using MVs produced by primary microglia. We found that MV lipids can promote formation of soluble Aβ species from extracellular insoluble aggregates. Moreover we showed that MVs can be carriers of neurotoxic Aβ forms that are trafficked to MVs after internalization into microglia. Neurotoxicity of MVs was neutralized by the Aβ interacting protein PrP and anti- Aβ antibodies, which prevented binding to neurons of neurotoxic soluble Aβ species. Finally, administration of the MV shedding inhibitor FTY720 for a period of 6 weeks significantly improved memory performance and reduced brain inflammation in APP/PS1 mice. This study identifies microglial MVs as a novel mechanism by which reactive microglia contribute to AD degeneration and suggests that FTY720, by inhibiting MV shedding can ameliorate the pathophisiology and cognitive defects in a mouse AD model.