Inflammasome activation in neurodegenerative diseases

Abstract

Approximately ten million people are diagnosed with dementia annually since they experience difficulties with memory and thinking skills. Since neurodegenerative diseases are diagnosed late, most of them are difficult to treat. This is due to the increased severity of the disease during the progression when neuroinflammation plays a critical role. The activation of immune cells, especially microglia, plays a crucial role in the development of neurodegenerative diseases. Molecular sensors within these microglia, such as the NLRP3 inflammasome, are activated by signals that represent the hallmarks of neurodegenerative diseases. Here, we first summarize the two activation steps of NLRP3 inflammasome activation. Furthermore, we discuss the key factors that contribute to NLRP3 inflammasome activation in the different neuroinflammatory diseases, like Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). The prominent NLRP3 inflammasome triggers include amyloid β and tau oligomers in AD, α-synuclein in PD, and superoxide dismutase (SOD1) and TAR DNA-binding protein 43 (TDP43) in ALS. NLRP3 inhibitor treatment has shown promising results in several preclinical mouse models of AD, PD, and ALS. Finally, we postulate that current understandings underpin the potential for NLRP3 inhibitors as a therapeutic target in neurodegenerative diseases.

Punicalagin Attenuates LPS-Induced Inflammation and ROS Production in Microglia by Inhibiting the MAPK/NF-κB Signaling Pathway and NLRP3 Inflammasome Activation

“…The activation of NLRP3 inflammasome has been demonstrated to associate with neuroinflammatory diseases including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. 26 , 27 To examine whether punicalagin affected NLRP3 inflammasome activation, BV2 cells were pre-treated with various doses of punicalagin for 30 min, primed with LPS for 47.5 h, and then stimulated with ATP or nigericin for 30 min. The secretion of IL-1β was analyzed by ELISA and the expression of inflammasome-associated proteins was examined using Western blot.…”

“… 34 , 47 , 48 Activation of NLRP3 inflammasome is associated with neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. 26 , 27 Neuroinflammation and activation of microglia around the degenerating neurons with subsequent secretion of proinflammatory molecule IL-1β lead to neuronal damage. 31 The canonical activation of the NLRP3 inflammasome, a multiprotein complex composed of NLRP3, ASC and caspase-1, is responsible for the production of IL-1β from microglia upon cellular stress as well as induction of pyroptosis, a type of programmed cell death that causes rupture of the cell membrane resulting in the release of more pro-inflammatory cytokines thereby promoting the inflammatory response.…”

Taohong siwu decoction attenuates AIM2 and NLRC4 inflammasomes by ameliorates deoxyribonucleic acid damage after ischemic stroke

“…When abnormal doublestranded DNA is present in the cytoplasm, the HIN domain of AIM2 binds to the cytoplasm double-stranded DNA in a sequence-independent manner. AIM2 can be activated by procaspase-1 cleavage (Ravichandran and Heneka, 2021). Activated caspase-1 cleaves pro-inflammatory cytokines such as pro-IL-1β and pro-IL-18 into mature forms of IL-1β and IL-18 and induces their release, which recruits other inflammatory cells and amplifies the inflammatory response (Broz and Dixit, 2016;Sun and Scott, 2016).…”

Inflammasome activation in traumatic brain injury and Alzheimer's disease

“…The NLRP1 sensor contains a function-to-find domain, and a C terminus caspase recruitment domain (CARD) and is activated by microbial associated agents such as Bacillus anthrax lethal toxin, changes in cellular ATP levels, and double stranded RNA [55]. NLRP1 binds caspase-1 directly or with the adapter, ASC [50,51,56,57]. The NLRP3 sensor is unique in that it is activated through numerous triggers and by two distinct pathways.…”