Proceedings of the National Academy of Sciences - PNAS, 2020-12, Vol.117 (50), p.32145-32154
2020
Details
- Autor(en) / Beteiligte
- Titel
- The NLRP3 inflammasome inhibitor OLT1177 rescues cognitive impairment in a mouse model of Alzheimer’s disease
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2020-12, Vol.117 (50), p.32145-32154
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2020
- Link zum Volltext
- Quelle
- EZB Electronic Journals Library
- Beschreibungen/Notizen
- Numerous studies demonstrate that neuroinflammation is a key player in the progression of Alzheimer’s disease (AD). Interleukin (IL)-1β is a main inducer of inflammation and therefore a prime target for therapeutic options. The inactive IL-1β precursor requires processing by the the nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome into a mature and active form. Studies have shown that IL-1β is up-regulated in brains of patients with AD, and that genetic inactivation of the NLRP3 inflammasome improves behavioral tests and synaptic plasticity phenotypes in a murine model of the disease. In the present study, we analyzed the effect of pharmacological inhibition of the NLRP3 inflammasome using dapansutrile (OLT1177), an oral NLRP3-specific inhibitor that is safe in humans. Six-month-old WT and APP/PS1 mice were fed with standard mouse chow or OLT1177-enriched chow for 3 mo. The Morris water maze test revealed an impaired learning and memory ability of 9-mo-old APP/PS1 mice (P = 0.001), which was completely rescued by OLT1177 fed to mice (P = 0.008 to untreated APP/PS1). Furthermore, our findings revealed that 3 mo of OLT1177 diet can rescue synaptic plasticity in this mouse model of AD (P = 0.007 to untreated APP/PS1). In addition, microglia were less activated (P = 0.07) and the number of plaques was reduced in the cortex (P = 0.03) following NLRP3 inhibition with OLT1177 administration. We also observed an OLT1177 dose-dependent normalization of plasma metabolic markers of AD to those of WT mice. This study suggests the therapeutic potential of treating neuroinflammation with an oral inhibitor of the NLRP3 inflammasome.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.2009680117Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7749353
- Format
- –
- Schlagworte
- Administration, Oral, Alzheimer Disease - complications, Alzheimer Disease - drug therapy, Alzheimer Disease - genetics, Alzheimer Disease - immunology, Alzheimer's disease, Amyloid beta-Protein Precursor - genetics, Animal models, Animals, Behavior Observation Techniques, Behavior, Animal - drug effects, Behavioral plasticity, Biological Sciences, Cerebral Cortex - drug effects, Cerebral Cortex - immunology, Cerebral Cortex - pathology, Cognitive ability, Cognitive Dysfunction - drug therapy, Cognitive Dysfunction - immunology, Cognitive Dysfunction - pathology, Disease Models, Animal, Domains, Humans, IL-1β, Inactivation, Inflammasomes, Inflammasomes - antagonists & inhibitors, Inflammasomes - immunology, Inflammation, Interleukins, Male, Maze learning, Mice, Mice, Transgenic, Microglia, Microglia - drug effects, Microglia - immunology, Microglia - pathology, Neurodegenerative diseases, Neuronal Plasticity - drug effects, Neuronal Plasticity - immunology, Nitriles - pharmacology, Nitriles - therapeutic use, NLR Family, Pyrin Domain-Containing 3 Protein - antagonists & inhibitors, NLR Family, Pyrin Domain-Containing 3 Protein - immunology, Nucleotides, Oligomerization, Phenotypes, Phenotypic plasticity, Plaques, Plasticity, Presenilin 1, Presenilin-1 - genetics, Pyrin protein, Spatial Memory - drug effects, Synaptic plasticity