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Review
. 2022 Feb 16:13:845185.
doi: 10.3389/fphar.2022.845185. eCollection 2022.

The Role of NLRP3 Inflammasome in Alzheimer's Disease and Potential Therapeutic Targets

Tao Liang  1 , Yang Zhang  1 , Suyuan Wu  1 , Qingjie Chen  2 , Lin Wang  1   3
Affiliations
Review

The Role of NLRP3 Inflammasome in Alzheimer's Disease and Potential Therapeutic Targets

Tao Liang et al. Front Pharmacol. .

Abstract

Alzheimer's disease (AD) is a common age-related neurodegenerative disease characterized by progressive cognitive dysfunction and behavioral impairment. The typical pathological characteristics of AD are extracellular senile plaques composed of amyloid ß (Aβ) protein, intracellular neurofibrillary tangles formed by the hyperphosphorylation of the microtubule-associated protein tau, and neuron loss. In the past hundred years, although human beings have invested a lot of manpower, material and financial resources, there is no widely recognized drug for the effective prevention and clinical cure of AD in the world so far. Therefore, evaluating and exploring new drug targets for AD treatment is an important topic. At present, researchers have not stopped exploring the pathogenesis of AD, and the views on the pathogenic factors of AD are constantly changing. Multiple evidence have confirmed that chronic neuroinflammation plays a crucial role in the pathogenesis of AD. In the field of neuroinflammation, the nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is a key molecular link in the AD neuroinflammatory pathway. Under the stimulation of Aβ oligomers and tau aggregates, it can lead to the assembly and activation of NLRP3 inflammasome in microglia and astrocytes in the brain, thereby causing caspase-1 activation and the secretion of IL-1β and IL-18, which ultimately triggers the pathophysiological changes and cognitive decline of AD. In this review, we summarize current literatures on the activation of NLRP3 inflammasome and activation-related regulation mechanisms, and discuss its possible roles in the pathogenesis of AD. Moreover, focusing on the NLRP3 inflammasome and combining with the upstream and downstream signaling pathway-related molecules of NLRP3 inflammasome as targets, we review the pharmacologically related targets and various methods to alleviate neuroinflammation by regulating the activation of NLRP3 inflammasome, which provides new ideas for the treatment of AD.

Keywords: Alzheimer’s disease; NLRP3 inflammasome; inflammation; mitochondrial dysfunction; neuroinflammation.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
A schematic diagram of the association between NLRP3 inflammasome activation and AD pathogenesis. Both Aβ oligomers and Tau aggregates are involved in the inflammatory response of AD. Fibrillar Aβ species are regarded as PAMPs that triggers NF-κB activation through pattern recognition receptors (such as TLRs) to elevate inflammasome components NLRP3 and pro-IL-1β. NLRP3, ASC, and pro-caspase-1 assemble together to form the NLRP3 inflammasome, which subsequently activates caspase-1, cleaves pro-IL-1β to produce the active form of IL-1β and secretes it extracellularly. In addition, phagocytosis of soluble Aβ also triggers lysosome leakage and consequently results in the emission of cathepsin B, which leads to NLRP3 inflammasome activation. Furthermore, Aβ oligomers can act as damaging stimulis to induce mitochondrial dysfunction, causing the production and accumulation of ROS, release of mtDNA, or cardiolipin externalization, which activates the NLRP3 inflammasome. Autophagy can not only clear Aβ, but also clear NLRP3, ASC and pro-caspase-1 inflammasome-related protein molecules. Mitophagy can selectively remove impaired mitochondria and relieve the release of damaging molecules within mitochondria. Therefore, autophagy and mitophagy can negatively regulate the activation of NLRP3. Aβ also indirectly regulate the activation of the NLRP3 inflammasome through the autophagy or mitophagy pathway. Moreover, the activation of NLRP3 inflammasome inhibits the phagocytosis of Aβ by glial cells, which contributes to the deposition of Aβ and facilitates the formation of Aβ plaques. In conclusion, Aβ can activate the NLRP3 inflammasome through different pathways. However, once the NLRP3 inflammasome is activated, it in turn increases the deposition of Aβ and the formation of Aβ plaque, which forms a positive feedback loop that amplifies Aβ pathogenic effect. Similar to the role of Aβ, Tau is regarded as an endogenous dangerous molecule that can activate the NLRP3 inflammasome. After the NLRP3 inflammasome is activated, it increases the activity of Tau kinase and phosphorylase, and facilitates the phosphorylation and aggregation of Tau, thereby also forming a positive feedback loop. Persistent activation of the NLRP3 inflammasome triggered by Aβ and Tau contributes to the development of chronic neuroinflammation, which ultimately leads to the neuronal loss and cognitive impairment. AD: Alzheimer’s disease; Aβ: amyoid β; PAMPs: pathogen-associated molecular patterns; TLRs: Toll-like receptors; NF-κB: nuclear factor kappa B; NLRP3: nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3; ASC: apoptosis-associated speck-like protein containing a CARD; ROS: reactive oxygen species; mtROS: mitochondrial ROS; mtDNA: mitochondrial DNA; MyD88: myeloid differentiation factor 88; GSDMD: gasdermin D.
FIGURE 2
FIGURE 2
Pharmacological targets of the NLRP3 inflammasome (LPS: lipopolysaccharide; TLR: Toll-like receptor; NF-κB: nuclear factor kappa B; mtROS: mitochondrial ROS; mtDNA: mitochondrial DNA; NLRP3: nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3; ASC: apoptosis-associated speck-like protein containing a CARD; PG: progesterone; TSG: 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside; Qu: Quercetin; MNS: 3,4-methylenedioxy-β-nitrostyrene; CARD: caspase recruitment domain; NACHT: nucleotide-binding and oligomerization domain; PYD: pyrin domain; LRR: leucine-rich repeat).
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