Soluble Aβ oligomers and protofibrils induce NLRP3 inflammasome activation in microglia. Issue 6 (30th January 2020)

• Record Type: Journal Article
• Authors: Lučiūnaitė, Asta; McManus, Róisín M.; Jankunec, Marija; Rácz, Ildikó; Dansokho, Cira; Dalgėdienė, Indrė; Schwartz, Stephanie; Brosseron, Frederic; Heneka, Michael T.
• Is Part Of: Journal of neurochemistry. Volume 155:Issue 6(2020)
• Page Start: 650
• Page End: 661
• Publication Date: 2020-01-30
• Subjects: Alzheimer -- ASC speck -- IL‐1β -- microglia -- NLRP3 inflammasome -- s disease -- soluble Aβ; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.14945
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: 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‐β (Aβ) and the formation of neurofibrillary tau tangles. Fibrillar Aβ 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 Aβ oligomers or protofibrils that represent lower molecular aggregates prior to Aβ deposition are able to activate the NLRP3 inflammasome and subsequent interleukin‐1 beta (IL‐1β) release by microglia. In our study, we used Aβ 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 Aβ preparations and NLRP3 inflammasome activation, represented by caspase‐1 cleavage, IL‐1β production, and apoptosis‐associated speck‐like protein containing a CARD speck formation was analysed. Both protofibrils and low molecular weight Aβ aggregates induced a significant increase in IL‐1β 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 Aβ‐induced immune response. Our results show that the NLRP3 inflammasome is activated not only by fibrillar Aβ aggregates as reported before, but also by lower molecular weight Aβ oligomers and protofibrils, highlighting the possibility that microglial activation by these Aβ species may initiate innate immune responses in the central nervous system prior to the onset of Aβ deposition. Cover Image for this issue: https://doi.org/10.1111/jnc.14773 . Abstract : Amyloid‐beta (Aβ) is recognized as a danger‐associated molecular pattern by pattern recognition receptors present on microglial cells. The aim of the study was to analyse whether low molecular weight Aβ oligomers that are more neurotoxic in comparison with fibrils, could activate NLRP3 inflammasome in microglial cells. Our results confirm that NLRP3 inflammasome is activated not only by fibrils forming Aβ aggregates but also by small oligomers. The inflammasome activation could be completely blocked by the specific inhibitor, MCC950. These results highlight that microglia activated by Aβ oligomers and protofibrils are potent drivers of neuroinflammatory processes. Cover Image for this issue: https://doi.org/10.1111/jnc.14773 .