Beta-amyloid activates NLRP3 inflammasome via TLR4 in mouse microglia.

Beta-amyloid(Aβ)-induced inflammation plays a critical role in the pathogenesis of Alzheimer's disease (AD). Nod-like receptor nucleotide-binding domain leucine rich repeat containing protein 3 (NLRP3) inflammasome is involved in the Aβ-induced inflammation. However, the mechanisms by which extracellular Aβ activates cytoplasmic NLRP3 inflammasome are poorly understood. Toll-like receptor 4(TLR4) acts as a sensor of Aβ and performs a key role in neuroinflammation. TLR4 is involved in activating the NLRP3 inflammasome in several diseases. In this study, the interaction between TLR4 and NLRP3 inflammasome in Aβ1-42-induced neuroinflammation was investigated. BV-2 microglia and primary microglia were primed with lipopolysaccharide (LPS) and then pretreated with TLR4 inhibitor CLI-095, followed by stimulation with Aβ1-42. The protein expression of NLRP3, the adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC), and caspase-1 p 10 was detected by western blotting and immunostaining. The mRNA expression of inflammatory factors was measured by real-time PCR. The protein level of pro IL-1β and IL-1β was examined by ELISA. Activated microglia were examined by immunofluorescence staining for ionized calcium-binding adapter molecule-1 (Iba-1). Conditioned medium of BV-2 cells was collected to challenge HT-22 neurons. Cell viability was assessed with MTT assay. Assessment of HT-22 cell apoptosis was performed by Annexin V/PI staining and western blotting to detect the protein level of cleaved caspase 3. The results showed that Aβ1-42 activated and up-regulated the expression of NLRP3 inflammasome in BV-2 microglia, as indicated by increased activation of caspase-1 and secretion of IL-1β. Pharmacological inhibition of TLR4 by CLI-095 abolished Aβ1-42-induced NLRP3 inflammasome activation, which curbed the development of inflammation and exerted protective effect on HT-22 neurons. Furthermore, the inhibitory effects of CLI-095 on Aβ1-42-induced inflammation were reversed by NLRP3 activator ATP. Overall, our findings suggested TLR4 mediated Aβ1-42-induced NLRP3 inflammasome activation in mouse microglia. TLR4/NLRP3 pathway plays a critical role in Aβ1-42-induced neuroinflammation.

Liu Y ，Dai Y ，Li Q ，Chen C ，Chen H ，Song Y ，Hua F ，Zhang Z ... -  《-》

TLR4/Rac1/NLRP3 Pathway Mediates Amyloid-β-Induced Neuroinflammation in Alzheimer's Disease.

Zhu M ，Liu Y ，Chen C ，Chen H ，Ni W ，Song Y ，Lv B ，Hua F ，Cui G ，Zhang Z ... -  《-》

α1-antitrypsin mitigates NLRP3-inflammasome activation in amyloid β(1-42)-stimulated murine astrocytes.

Ebrahimi T ，Rust M ，Kaiser SN ，Slowik A ，Beyer C ，Koczulla AR ，Schulz JB ，Habib P ，Bach JP ... -  《Journal of Neuroinflammation》

Melatonin Attenuates LPS-Induced Acute Depressive-Like Behaviors and Microglial NLRP3 Inflammasome Activation Through the SIRT1/Nrf2 Pathway.

Arioz BI ，Tastan B ，Tarakcioglu E ，Tufekci KU ，Olcum M ，Ersoy N ，Bagriyanik A ，Genc K ，Genc S ... -  《Frontiers in Immunology》

Targeting the NLRP3 Inflammasome-Related Pathways via Tianeptine Treatment-Suppressed Microglia Polarization to the M1 Phenotype in Lipopolysaccharide-Stimulated Cultures.

Ślusarczyk J ，Trojan E ，Głombik K ，Piotrowska A ，Budziszewska B ，Kubera M ，Popiołek-Barczyk K ，Lasoń W ，Mika J ，Basta-Kaim A ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》