Soluble A Beta Oligomers And Protofibrils Induce Nlrp3 Inflammasome Activation In Microglia

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder causing memory loss, language problems and behavioural disturbances. AD is associated with the accumulation of fibrillar amyloid-beta (A beta) and the formation of neurofibrillary tau tangles. Fibrillar A beta itself represents a danger-associated molecular pattern, which is recognized by specific microglial receptors. One of the key players is formation of the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome, whose activation has been demonstrated in AD patient brains and transgenic animal models of AD. Here, we investigated whether A beta oligomers or protofibrils that represent lower molecular aggregates prior to A beta deposition are able to activate the NLRP3 inflammasome and subsequent interleukin-1 beta (IL-1 beta) release by microglia. In our study, we used A beta preparations of different sizes: small oligomers and protofibrils of which the structure was confirmed by atomic force microscopy. Primary microglial cells from C57BL/6 mice were treated with the respective A beta preparations and NLRP3 inflammasome activation, represented by caspase-1 cleavage, IL-1 beta production, and apoptosis-associated speck-like protein containing a CARD speck formation was analysed. Both protofibrils and low molecular weight A beta aggregates induced a significant increase in IL-1 beta release. Inflammasome activation was confirmed by apoptosis-associated speck-like protein containing a CARD speck formation and detection of active caspase-1. The NLRP3 inflammasome inhibitor MCC950 completely inhibited the A beta-induced immune response. Our results show that the NLRP3 inflammasome is activated not only by fibrillar A beta aggregates as reported before, but also by lower molecular weight A beta oligomers and protofibrils, highlighting the possibility that microglial activation by these A beta species may initiate innate immune responses in the central nervous system prior to the onset of A beta deposition.