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Review
. 2022 Aug 11;23(16):8979.
doi: 10.3390/ijms23168979.

Targeting NLRP3-Mediated Neuroinflammation in Alzheimer's Disease Treatment

Julia Barczuk  1 , Natalia Siwecka  1 , Weronika Lusa  1 , Wioletta Rozpędek-Kamińska  1 , Ewa Kucharska  2 , Ireneusz Majsterek  1
Affiliations
Review

Targeting NLRP3-Mediated Neuroinflammation in Alzheimer's Disease Treatment

Julia Barczuk et al. Int J Mol Sci. .

Abstract

Alzheimer's disease (AD) is the most common cause of dementia in the general population and, to date, constitutes a major therapeutic challenge. In the pathogenesis of AD, aggregates of amyloid β (Aβ) and neurofibrillary tangles (NFTs) containing Tau-microtubule-associated protein (tau) are known to trigger a neuroinflammatory response with subsequent formation of an inflammasome. In particular, the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome is thought to play a crucial role in AD-related pathology. While the mechanisms for NLRP3 activation are not fully understood, it has been demonstrated that, after detection of protein aggregates, NLRP3 induces pro-inflammatory cytokines, such as interleukin 18 (IL-18) or interleukin 1β (IL-1β), that further potentiate AD progression. Specific inhibitors of NLRP3 that exhibit various mechanisms to attenuate the activity of NLRP3 have been tested in in vivo studies and have yielded promising results, as shown by the reduced level of tau and Aβ aggregates and diminished cognitive impairment. Herein, we would like to summarize the current state of knowledge on NLRP3 inflammasome priming, activation, and its actual role in AD pathogenesis, and to characterize the NLRP3 inhibitors that have been studied most and their impact on AD-related pathology.

Keywords: Alzheimer’s disease; Alzheimer’s disease treatment; NOD-like receptor pyrin domain-containing 3; NOD-like receptor pyrin domain-containing 3 inflammasome; NOD-like receptor pyrin domain-containing 3 inhibitors; amyloid β; neurofibrillary tangles.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The mechanisms of priming and activation of the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome. Firstly, protein aggregates (Aβ and tau) are recognized by microglial pattern recognition receptors, such as Toll-like receptors (e.g., TLR2, TLR4), or cluster of differentiation 36 (CD36). Afterwards, they induce activation of specific pathways like MYD88/NF-κB, which leads to transcription of pro-IL-β and NLRP3. One of the NLRP3 domains—the adaptor molecule apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)—recruits pro-caspase-1, which enables the release of inflammatory cytokines, namely IL-18 and IL-β. Further, cell death in the form of pyroptosis occurs after the activation of NLRP3 via the induction of gasdemin D (GSDMD). GSDMD can induce membrane-disrupting cytotoxicity and facilitates the secretion of inflammatory cytokines via the creation of pores in the cell membrane.
Figure 2
Figure 2
The factors inducing NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome activation in the pathogenesis of AD. The recognition of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) by specific cellular receptors may bring NLRP3 into the active state. Activation may also be triggered by factors related to cell damage, which involve mitochondrial disruption with the overproduction of reactive oxygen species (ROS) and mitochondrial DNA (mtDNA) release, necrosis with an increased level of ATP released from damaged cells, ion dysregulation (K+ efflux and Ca2+ influx), and lysosomal destabilization resulting from impaired microglial phagocytosis. Furthermore, protein deposits of Tau and amyloid β (Aβ) may drive lysosomal dysfunction due to their resistance to degradation, and may also directly induce NLRP3 activation. Additionally, UV radiation constitutes another independent factor for activation of the NLRP3 inflammasome.
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