[en] 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.
Disciplines :
Neurology
Author, co-author :
Lučiūnaitė, Asta ; Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania ; Department of Neurodegenerative Disease and Geriatric Psychiatry, Bonn, Germany ; German Center for Neurodegenerative Disease (DZNE), Bonn, Germany
McManus, Róisín M ; Department of Neurodegenerative Disease and Geriatric Psychiatry, Bonn, Germany ; German Center for Neurodegenerative Disease (DZNE), Bonn, Germany
Jankunec, Marija; Institute of Biochemistry, Life Sciences Center, Vilnius University, Vilnius, Lithuania
Rácz, Ildikó ; Department of Neurodegenerative Disease and Geriatric Psychiatry, Bonn, Germany
Dansokho, Cira; Department of Neurodegenerative Disease and Geriatric Psychiatry, Bonn, Germany ; German Center for Neurodegenerative Disease (DZNE), Bonn, Germany
Dalgėdienė, Indrė ; Institute of Biotechnology, Life Sciences Center, Vilnius University, Vilnius, Lithuania
Schwartz, Stephanie; Department of Neurodegenerative Disease and Geriatric Psychiatry, Bonn, Germany
Brosseron, Frederic; German Center for Neurodegenerative Disease (DZNE), Bonn, Germany
HENEKA, Michael ; Department of Neurodegenerative Disease and Geriatric Psychiatry, Bonn, Germany
External co-authors :
yes
Language :
English
Title :
Soluble Aβ oligomers and protofibrils induce NLRP3 inflammasome activation in microglia.
This study was supported by the University of Bonn. M. Heneka is member of Excellence Cluster 2. We thank Dr Jochen Walter for fruitful discussions. M. Heneka: Clinical advisory board member at IFM Therapeutics, scientific advisory board member at Alector. He holds editorship at the J. Neurochemistry, and received honoraria for oral presentations from Pfizer, Novartis, Roche, Abbvie and Biogen. The graphical abstract was prepared using BioRender. All experiments were conducted in compliance with the ARRIVE guidelines.This study was supported by the University of Bonn. M. Heneka is member of Excellence Cluster 2. We thank Dr Jochen Walter for fruitful discussions. M. Heneka: Clinical advisory board member at IFM Therapeutics, scientific advisory board member at Alector. He holds editorship at the , and received honoraria for oral presentations from Pfizer, Novartis, Roche, Abbvie and Biogen. The graphical abstract was prepared using BioRender. J. Neurochemistry
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