Alzheimer's disease; Aβ; NLRP3 inflammasome; antisense oligonucleotides; innate immunity; microglia; neuroinflammation; Biochemistry; Cellular and Molecular Neuroscience; A beta
Abstract :
[en] Alzheimer's disease (AD) is associated with the cerebral deposition of Amyloid-β (Aβ) peptide, which leads to NLRP3 inflammasome activation and subsequent release of interleukin-1β (IL-1β) and interleukin-18 (IL-18). NLRP3 reduction has been found to increase microglial clearance, protect from synapse loss, and suppress both the changes to synaptic plasticity and spatial memory dysfunction observed in murine AD models. Here, we test whether NLRP3-directed antisense oligonucleotides (ASOs) can be harnessed as immune modulators in primary murine microglia and human THP-1 cells. NLRP3 mRNA degradation was achieved at 72 h of ASO treatment in primary murine microglia. Consequently, NLRP3-directed ASOs significantly reduced the levels of cleaved caspase-1 and mature IL-1β when microglia were either activated by LPS and nigericin or LPS and Aβ. In human THP-1 cells NLRP3-targeted ASOs also significantly reduced the LPS plus nigericin- or LPS plus Aβ-induced release of mature IL-1β. Together, NLRP3-directed ASOs can suppress NLRP3 inflammasome activity and subsequent release of IL-1β in primary murine microglia and THP-1 cells. ASOs may represent a new and alternative approach to modulate NLRP3 inflammasome activation in neurodegenerative diseases, in addition to attempts to inhibit the complex pharmacologically.
Disciplines :
Life sciences: Multidisciplinary, general & others Biochemistry, biophysics & molecular biology Neurology
Author, co-author :
Braatz, Charlotte ; Institute for Innate Immunity, University of Bonn, Bonn, Germany
Komes, Max P; Institute for Innate Immunity, University of Bonn, Bonn, Germany
Ravichandran, Kishore Aravind ; Institute for Innate Immunity, University of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
de Fragas, Matheus Garcia ; Institute for Innate Immunity, University of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany ; Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
Griep, Angelika ; Institute for Innate Immunity, University of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Schwartz, Stephanie; Institute for Innate Immunity, University of Bonn, Bonn, Germany
McManus, Róisín M ; Institute for Innate Immunity, University of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
HENEKA, Michael ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) ; Institute for Innate Immunity, University of Bonn, Bonn, Germany ; Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
External co-authors :
yes
Language :
English
Title :
NLRP3-directed antisense oligonucleotides reduce microglial immunoactivities in vitro.
Alzheimer Forschung Initiative Deutsche Forschungsgemeinschaft Deutscher Akademischer Austauschdienst
Funding text :
We thank I. Rácz for help with laboratory administration and S. Opitz and F. Santarelli for technical assistance. This work was funded by Deutscher Akademischer Austauschdienst, (Grant / Award Number: 'scholarship') Alzheimer Forschung Initiative, (Grant / Award Number: '20043') Deutsche Forschungsgemeinschaft, (Grant / Award Number: 'EXC2151 – 390873048 ') BONFOR research commission of the medical faculty of the University of Bonn, (Grant / Award Number: '2021‐4‐06'). Open Access funding enabled and organized by Projekt DEAL.
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