Ginsenoside Rg1 alleviates Aβ deposition and neuronal damage by inhibiting NLRP1 inflammasome activation in APP/PS1 mice

Abstract Background: Oxidative stress and neuroinflammation play important roles in the whole pathogenesis of Alzheimer's disease (AD). NADPH oxidase 2 (NOX2) is an important enzyme that is responsible for ROS generation in many neurodegenerative diseases. The nucleotide-binding oligomerization domain (NOD)-like receptor protein 1 (NLRP1) inflammasome is responsible for the formation of pro-inflammatory molecules in neurons. However, it is still unclear whether inhibition of NOX2 and NLRP1 inflammasome decreases amyloid-beta (Aβ) generation and deposition in APP/PS1 mice. Ginsenoside Rg1 (Rg1) is an active component in ginseng, and maybe a potential agent for neurodegenerative diseases. In this study, we investigated the effects and mechanisms of Rg1 treatment on cognitive performance, neuronal damage, Aβ deposition and NOX2-NLRP1 inflammasome activation in APP/PS1 mice.Methods: WT and APP/PS1 mice were used in the experiment from 6 months (M) old to 9M old, and 6M APP/PS1 mice were used as pre-treatment controls. The open field test (OFT) and Morris water maze (MWM) were used to detect behavioral change and cognitive function. The H&E and Nissl staining were used to assess neuronal damage. We further examined PSD95 expression, Aβ generation and deposition, Tau and p-Tau expression, NOX2-mediated ROS generation and NLRP1 inflammasome activation by using immunofluorescence, western blot analysis, and real time q-PCR.Results: Rg1 treatment for 12 weeks alleviated learning and memory impairments and neuronal damage, decreased p-Tau level, APP expression and Aβ deposition in APP/PS1 mice. Meanwhile, Rg1 treatment significantly decreased the levels of ROS and IL-1β, and reduced the expressions of NOX2 and NLRP1 inflammasome in the brain cortex and hippocampus in APP/PS1 mice. Furthermore, apocynin (a NOX inhibitor) and NLRP1-siRNA treatment also alleviated cognitive impairments, neuronal damage and Aβ deposition, and reduced the expression of NLRP1 inflammasome in brain cortex and hippocampus in APP/PS1 mice.Conclusions: Rg1 treatment could alleviate learning and memory impairment, neuronal damage, and reduce Aβ generation and deposition by inhibiting NLRP1 inflammasome activation in APP/PS1 mice.