A novel strategy for bioactive natural products targeting NLRP3 inflammasome in Alzheimer's disease

Abstract

Alzheimer's disease (AD), the most common type of dementia, is an ageing-related progressive neurodegenerative brain disorder. Extracellular neuritic plaques composed of misfolded amyloid β (Aβ) proteins and intracellular neurofibrillary tangles formed by hyperphosphorylated tau protein are the two classical characteristics of AD. Aβ and tau pathologies induce neurite atrophy and neuronal apoptosis, leading to cognitive, language, and behavioral deficits. For decades, researchers have made great efforts to explore the pathogens and therapeutics of AD; however, its intrinsic mechanism remains unclear and there are still no well-established strategies to restore or even prevent this disease. Therefore, it would be beneficial for the establishment of novel therapeutic strategy to determine the intrinsic molecular mechanism that is interrelated with the initiation and progression of AD. A variety of evidence indicates that neuroinflammation plays a crucial role in the pathogenesis of AD. Nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) is a key inflammasome sensor of cellular stress and infection that is involved in the innate immune system. In response to a wide range of stimuli like Aβ, NLRP3 assembles apoptosis-associated speck-like protein (ASC) and procaspase-1 into an inflammasome complex to induce the caspase-1 mediated secretion of interleukin (IL)-1β/IL-18 in M1 polarized microglia, triggering the pathophysiological changes and cognitive decline of AD. Therefore, targeting NLRP3 inflammasome seems an efficient path for AD treatment via regulating brain immune microenvironment. Furthermore, accumulating evidence indicates that traditional Chinese medicine (TCM) exerts beneficial effects on AD via NLRP3 inflammasome inactivation. In this review, we summarize current reports on the role and activated mechanisms of the NLRP3 inflammasome in the pathogenesis of AD. We also review the natural products for attenuating neuroinflammation by targeting NLRP3 inflammasome activation, which provides useful clues for developing novel AD treatments.

Keywords: Alzheimer’s disease; NLRP3 inflammasome; microglia polarization; natural products; neuroinflammation.

FIGURE 1

Possible mechanisms of NLRP3 activation in microglia. In the initiation signal, Aβ fibrils bind to TLR, and drive the transcription of NLRP3, pro-IL-1β, and pro-IL-18 via NF-κB signaling. In the activating signal, the lysosomal-rupture pathway and ROS generation pathway are the two classical routes for NLRP3-mediated caspase-1 activation. The phagocytosis of aggregated Aβ by microglia triggers lysosomal rupture and the subsequent release of cathepsin B into the cytosol. In addition, Aβ triggers Ca2⁺ influx via TRPM2 and activates NADPH oxidase and Syk, subsequently inducing mitochondrial fragmentation and the generation of ROS. Therefore, the stimuli—including ROS and cathepsin B—drive the dispersed transGolgi network (dTGN) to recruit NLRP3 through ionic bonding, leading to adaptor protein ASC polymerization and downstream signaling activation.

FIGURE 2

The role of NLRP3 inflammasome in the pathophysiological processes of Alzheimer’s disease (AD). Aβ drives a microglial switch from the protective M2 to the inflammatory M1 phenotypes after binding with TLR4, while NLRP3 knockout reverses it. M1 microglia show decreased phagocytosis ability and low expression of Aβ degradation enzymes, leading to Aβ deposits. Meanwhile, secreted ASC specks from pyroptotic microglia bind to Aβ and seed the surrounding cells to further Aβ aggregation. IL-1β released from M1 microglia enhances the activity of GSK-3β and CaMKIIα enzymes and inhibits PP2A activity in neurons, with phosphorylate tau forming paired helical filament (PHF)-tau and neuronal fibrillary tangles.