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Mechanisms of NLRP3 Inflammasome Activation: Its Role in the Treatment of Alzheimer’s Disease

Neurochemical Research volume 45, pages 2560–2572 (2020)Cite this article

Abstract

Alzheimer’s disease (AD) is a common neurodegenerative disease of progressive dementia which is characterized pathologically by extracellular neuritic plaques containing aggregated amyloid beta (Aβ) and intracellular hyperphosphorylated tau protein tangles in cerebrum. It has been confirmed that microglia-specific nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome-mediated chronic neuroinflammation plays a crucial role in the pathogenesis of AD. Stimulated by Aβ deposition, NLRP3 assembles and activates within microglia in the AD brain, leading to caspase-1 activation along with downstream interleukin (IL)-1β secretion, and subsequent inflammatory events. Activation of the NLRP3 inflammasome mediates microglia to exhibit inflammatory M1 phenotype, with high expression of caspase-1 and IL-1β. This leads to Aβ deposition and neuronal loss in the amyloid precursor protein (APP)/human presenilin-1 (PS1) mouse model of AD. However, NLRP3 or caspase-1 deletion in APP/PS1 mice promotes microglia to transform to an anti-inflammatory M2 phenotype, with decreased secretion of caspase-1 and IL-1β. It also results in improved cognition, enhanced Aβ clearance, and a lower cerebral inflammatory response. This result suggests that the NLRP3 inflammasome may be an appropriate target for reducing neuroinflammation and alleviating pathological processes in AD. In the present review, we summarize the generally accepted regulatory mechanisms of NLRP3 inflammasome activation, and explore its role in neuroinflammation. Furthermore, we speculate on the possible roles of microglia-specific NLRP3 activation in AD pathogenesis and consider potential therapeutic interventions targeting the NLRP3 inflammasome in AD.

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Affiliations

  1. Department of Geriatrics, Second Hospital of Hebei Medical University, 215 Hepingxi Road, Shijiazhuang, Hebei, 050000, People’s Republic of China

    Yidan Zhang, Yuan Zhao, Jian Zhang & Guofeng Yang

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  1. Yidan Zhang
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  2. Yuan Zhao
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  3. Jian Zhang
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  4. Guofeng Yang
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GY contributed to the review idea, YZ contributed to the paper draft and revision, YZ and JZ contributed to the literature search. All authors read and approved the final manuscript.

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Correspondence to Guofeng Yang.

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Zhang, Y., Zhao, Y., Zhang, J. et al. Mechanisms of NLRP3 Inflammasome Activation: Its Role in the Treatment of Alzheimer’s Disease. Neurochem Res 45, 2560–2572 (2020). https://doi.org/10.1007/s11064-020-03121-z

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  • DOI: https://doi.org/10.1007/s11064-020-03121-z

Keywords

  • Alzheimer’s disease
  • Amyloid beta
  • NLRP3 inflammasome
  • Microglia
  • Neuroinflammation
  • NLRP3-associated intervention