Targeting NLRP3-Mediated Neuroinflammation in Alzheimer’s Disease Treatment

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.

Microglial autophagy in Alzheimer’s disease and Parkinson’s disease

“…In monocytes of AD patients, the mRNA and protein levels of NLRP3 are significantly increased ( Saresella et al, 2016 ), and NLRP1 is activated in the hippocampus of AD patients ( Španić et al, 2022 ). The abnormal Aβ and Tau induce inflammation through specific pathways involving MYD88 or NF-κB ( Yang et al, 2020 ; Barczuk et al, 2022 ), leading to the transcription of pro-IL-β and NLRP3 ( Lee J. H. et al, 2021 ; Leng and Edison, 2021 ). Increasing evidence has shown that soluble Aβ oligomers can activate the NLRP3 inflammasome in microglia ( Lučiūnaitė et al, 2020 ), while deletion or inhibition of NLRP3 in APP/PS1 in mice will reduce spatial memory loss and Aβ aggregation ( Michael et al, 2012 ; Dempsey et al, 2017 ; Feng et al, 2018 ).…”

Adipose tissue as a therapeutic target for vascular damage in Alzheimer's disease

“…In vivo studies testing specific inhibitors of NLRP3 have yielded promising results, such as a decrease of tau and Aβ aggregates and amelioration of the cognitive impairment (Barczuk et al, 2022). Small‐molecule NLRP3 inhibitors such as MCC950 have been shown to improve cognitive function and reduce Aβ accumulation (Dempsey et al, 2017; X. F. He et al, 2020).…”

The discovery of NLRP3 and its function in cryopyrin‐associated periodic syndromes and innate immunity

“…Beyond these disorders, the role of NLRP3 and its downstream effects through IL‐1 have been implicated in nearly every organ in humans. While some are perhaps more obvious given clear associations with known inflammasome triggers such as in silicosis 167 or asbestosis, 168 others such as neurodegenerative disorders 169 and ovarian aging 153 have been linked to excess NLRP3 activation and expression (Figure 8). For these challenging disorders, inhibitors of NLRP3 have been shown to reduce inflammation in vitro and in vivo, lending new opportunities for intervention.…”