A Novel Inhibitor Targeting NLRP3 Inflammasome Reduces Neuropathology and Improves Cognitive Function in Alzheimer’s Disease Transgenic Mice

Abstract

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, and the most common type of dementia. A growing body of evidence has implicated neuroinflammation as an essential player in the etiology of AD. Inflammasomes are intracellular multiprotein complexes and essential components of innate immunity in response to pathogen- and danger-associated molecular patterns. Among the known inflammasomes, the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays a critical role in the pathogenesis of AD. Objective: We recently developed a novel class of small molecule inhibitors that selectively target the NLRP3 inflammasome. One of the lead compounds, JC124, has shown therapeutic efficacy in a transgenic animal model of AD. In this study we will test the preventative efficacy of JC124 in another strain of transgenic AD mice. Methods: In this study, 5-month-old female APP/PS1 and matched wild type mice were treated orally with JC124 for 3 months. After completion of treatment, cognitive functions and AD pathologies, as well as protein expression levels of synaptic proteins, were assessed. Results: We found that inhibition of NLRP3 inflammasome with JC124 significantly decreased multiple AD pathologies in APP/PS1 mice, including amyloid-β (Aβ) load, neuroinflammation, and neuronal cell cycle re-entry, accompanied by preserved synaptic plasticity with higher expression of pre- and post-synaptic proteins, increased hippocampal neurogenesis, and improved cognitive functions. Conclusion: Our study demonstrates the importance of the NLRP3 inflammasome in AD pathological development, and pharmacological inhibition of NLRP3 inflammasome with small molecule inhibitors represents a potential therapy for AD.

Saffron extract and crocin exert anti-inflammatory and anti-oxidative effects in a repetitive mild traumatic brain injury mouse model

“…The obtained data reasonably explains the emergence of cognitive and motor deficits in our model, as inflammation is associated with such elicited acute disturbances following TBI 63 – 66 . Sirtuin 1 (SIRT1) is also an essential element for normal cognitive function and synaptic plasticity 67 and proved to enhance cognitive dysfunction in many studies 68 , 69 . The measured SIRT1 levels were also suppressed post TBI 43 .…”

Salidroside Ameliorates Alzheimer's Disease by Targeting NLRP3 Inflammasome-Mediated Pyroptosis

“…Then, Chiu et al (2021) found that SG-Tang could act as a neuroprotective agent against Aβ aggregation and neuroinflammation by regulating the NLRP1/NLRP3 pathway. Subsequently, Kuwar et al (2021) suggested that loaded Aβ can be reduced significantly, alleviate neuroinflammation, improve hippocampal neuronal activity, and relieve cognitive function in APP/PS1 mice via inhibiting NLRP3 inflammasome with JC124. Even though limited studies have probed the role and underlying mechanism of NLRP3 inflammasome-mediated pyroptosis in AD, the mechanisms of how NLRP3 inflammasome drive pyroptosis need further study.…”

Modulatory Properties of Food and Nutraceutical Components Targeting NLRP3 Inflammasome Activation

“…As an example, fatty acid caused by a high-fat diet activates the NLRP3 inflammasome through the molecular axis AMPK–autophagy–NF-kB-ROS [ 7 ]. Moreover, Amyloid β, post-translational modifications of NLRP3, and non-canonical inflammasome activations have been reported as triggers for the NLRP3 inflammasome [ 10 , 11 , 12 ].…”