Journal Article

DZNE-2023-00413

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png NLRP3-directed antisense oligonucleotides reduce microglial immunoactivities in vitro.

Braatz, C.Extern* ; Komes, M.Extern* ; Ravichandran, K.DZNE* ; Garcia de Fragas, M.DZNE* ; Griep, A.DZNE* ; Schwartz, S.Extern* ; McManus, R. (Last author)DZNE* ; Heneka, M. T. (Last author)DZNE*

2024
Wiley-Blackwell Oxford

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Please use a persistent id in citations: doi:10.1111/jnc.15778

Abstract: 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.

Keyword(s): Microglia: metabolism (MeSH) ; Microglia: drug effects (MeSH) ; Animals (MeSH) ; NLR Family, Pyrin Domain-Containing 3 Protein: metabolism (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; Oligonucleotides, Antisense: pharmacology (MeSH) ; Mice, Inbred C57BL (MeSH) ; Amyloid beta-Peptides: metabolism (MeSH) ; Interleukin-1beta: metabolism (MeSH) ; Inflammasomes: metabolism (MeSH) ; THP-1 Cells (MeSH) ; Cells, Cultured (MeSH) ; Alzheimer's disease ; Aβ ; NLRP3 inflammasome ; antisense oligonucleotides ; innate immunity ; microglia ; neuroinflammation

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Contributing Institute(s):

1. Interventional Trials and Biomarkers in Neurodegenerative Diseases (Biomarker)
2. Neuroinflammation, Biomarker (AG Heneka)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2023

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF < 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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