The application of NLRP3 inflammasome inhibition in Alzheimer’s disease therapeutics: Clinical benefits, applications, current limitations, and future development

Research Article
Open access

The application of NLRP3 inflammasome inhibition in Alzheimer’s disease therapeutics: Clinical benefits, applications, current limitations, and future development

Ziyu Yan 1*
  • 1 Tsinglan School    
  • *corresponding author 20260123@tsinglan.cn
Published on 20 December 2023 | https://doi.org/10.54254/2753-8818/20/20230795
TNS Vol.20
ISSN (Print): 2753-8826
ISSN (Online): 2753-8818
ISBN (Print): 978-1-83558-213-8
ISBN (Online): 978-1-83558-214-5

Abstract

The severe dementia Alzheimer’s Disease (AD) has been a neurodegenerative disorder that has troubled many for years due to its difficulty in therapeutic development. Negative regulation of the expression and activation of the NLRP3 inflammasome situated in the hippocampus, entorhinal cortex, blood, and other brain-connected tissues have been reported to contribute to the decrease of pathology and effect of AD. This concise review focuses on the various applications, characteristics, efficacy, and potential of inhibitors of the NLRP3 inflammasome at different stages of the NLRP3 activation and expression pathway in addition to their various limitations that would be places of improvement in future pharmaceutical development. NLRP3 inflammasomes such as IC100 and MCC950 are still in a stage of development, with advantages of high specificity and a large range of function, but with a variety of limiting factors such as the lack of clinical trials and deciding studies, therefore causing a therapy with large potential to be still in a position needing great progress.

Keywords:

Alzheimer’s Disease, NLRP3 inflammasome inhibition, IC100, ODZ10117

Yan,Z. (2023). The application of NLRP3 inflammasome inhibition in Alzheimer’s disease therapeutics: Clinical benefits, applications, current limitations, and future development. Theoretical and Natural Science,20,273-280.
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References

[1]. Zhang, Y., Zhao, Y., Zhang, J. and Yang, G., "Mechanisms of NLRP3 Inflammasome Activation: Its Role in the Treatment of Alzheimer’s Disease", Neurochem. Res. 45, 2560–2572 (2020).

[2]. Coll, R. C. et al, "MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition", Nat. Chem. Biol. 15, 556–559 (2019).

[3]. Stancu, I.-C. et al, "Aggregated Tau activates NLRP3–ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo", Acta Neuropathol. (Berl.) 137, 599–617 (2019).

[4]. Qi, Y., Klyubin, I., Ondrejcak, T., Hu, N.-W. and Rowan, M. J., "Enduring glucocorticoid-evoked exacerbation of synaptic plasticity disruption in male rats modelling early Alzheimer’s disease amyloidosis," Neuropsychopharmacology 46, 2170–2179 (2021).

[5]. Jia, L. et al, " Inhibition of NLRP3 alleviated chemotherapy-induced cognitive impairment in rats," Neurosci. Lett. 793, 136975 (2023).

[6]. Lonnemann, N. et al, "The NLRP3 inflammasome inhibitor OLT1177 rescues cognitive impairment in a mouse model of Alzheimer’s disease", Proc. Natl. Acad. Sci. U. S. A. 117, 32145–32154 (2020).

[7]. Haneklaus, M. et al, "Cutting edge: miR-223 and EBV miR-BART15 regulate the NLRP3 inflammasome and IL-1β production," J. Immunol. Baltim. Md 1950 189, 3795–3799 (2012).

[8]. Campani, V. et al, "Hybrid lipid self-assembling nanoparticles for brain delivery of microRNA", Int. J. Pharm. 588, 119693 (2020).

[9]. Mancuso, R. et al, " Circulatory miR-223-3p Discriminates Between Parkinson's and Alzheimer's Patients", Sci Rep. 28, 9(1), 9393 (2019)

[10]. de Rivero Vaccari, J. P. et al, "Mechanism action of IC 100, a humanized IgG4 monoclonal antibody targeting apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)", Transl Res. 251, 27–40 (2023).

[11]. Dick, M., Sborgi, L., Rühl, S., Hiller, S. and Broz, P, "ASC filament formation serves as a signal amplification mechanism for inflammasomes", Nat. Commun. 7, 11929 (2016).

[12]. Vontell, R. T. et al, "Identification of inflammasome signaling proteins in neurons and microglia in early and intermediate stages of Alzheimer’s disease", Brain Pathol. Zurich Switz. e13142 (2022).

[13]. Kang, J.-H. et al, "Novel Activity of ODZ10117, a STAT3 Inhibitor, for Regulation of NLRP3 Inflammasome Activation", Int. J. Mol. Sci. 24, 6079 (2023).

[14]. He, Y., Zeng, M. Y., Yang, D., Motro, B. and Núñez, G, "NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux", Nature 530, 354–357 (2016).

[15]. Jang, A.-R., Lee, H.-N., Hong, J. J., Kim, Y.-M. Park, J.-H., "Ethanol extract of Chrysanthemum zawadskii inhibits the NLRP3 inflammasome by suppressing ASC oligomerization in macrophages", Exp. Ther. Med. 25, 128 (2023).

[16]. Jayabalan, N. et al, "A Review of RRx-001: A Late-Stage Multi-Indication Inhibitor of NLRP3 Activation and Chronic Inflammation", Drugs 83, 389–402 (2023).

[17]. Reid, T., Oronsky, B., Caroen, S. and Cabrales, P., "The direct NLRP3 inhibitor and Phase 3 small molecule anticancer agent, RRx-001, protects aged triple transgenic Alzheimer’s disease model mice from CNS degeneration and cognitive decline", Alzheimers Dement. 18, e061516 (2022).

[18]. Youm, Y.-H. et al, "The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome–mediated inflammatory disease", Nat. Med. 21, 263–269 (2015).

[19]. Shippy, D.-C. et al, " β-Hydroxybutyrate inhibits inflammasome activation to attenuate Alzheimer’s disease pathology", J. Neuroinflammation 21;17(1):280 (2020)

[20]. Kuwar, R. et al, "A Novel Inhibitor Targeting NLRP3 Inflammasome Reduces Neuropathology and Improves Cognitive Function in Alzheimer’s Disease Transgenic Mice", J. Alzheimers Dis. 82, 1769–1783 (2021).

[21]. Zhang, C. et al, "Targeting NLRP3 signaling by a novel-designed sulfonylurea compound for inhibition of microglial inflammation", Bioorg. Med. Chem. 58, 116645 (2022).

[22]. Wang, B. et al, "Structural Proteomic Profiling of Cerebrospinal Fluids to Reveal Novel Conformational Biomarkers for Alzheimer’s Disease", J. Am. Soc. Mass Spectrom. 34, 459–471 (2023).

[23]. Mu, X. et al, "A novel label-free universal biosensing platform based on CRISPR/Cas12a for biomarker detection", Talanta 251, 123795 (2023).


Cite this article

Yan,Z. (2023). The application of NLRP3 inflammasome inhibition in Alzheimer’s disease therapeutics: Clinical benefits, applications, current limitations, and future development. Theoretical and Natural Science,20,273-280.

Data availability

The datasets used and/or analyzed during the current study will be available from the authors upon reasonable request.

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About volume

Volume title: Proceedings of the 3rd International Conference on Biological Engineering and Medical Science

ISBN:978-1-83558-213-8(Print) / 978-1-83558-214-5(Online)
Editor:Alan Wang
Conference website: https://www.icbiomed.org/
Conference date: 2 September 2023
Series: Theoretical and Natural Science
Volume number: Vol.20
ISSN:2753-8818(Print) / 2753-8826(Online)

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References

[1]. Zhang, Y., Zhao, Y., Zhang, J. and Yang, G., "Mechanisms of NLRP3 Inflammasome Activation: Its Role in the Treatment of Alzheimer’s Disease", Neurochem. Res. 45, 2560–2572 (2020).

[2]. Coll, R. C. et al, "MCC950 directly targets the NLRP3 ATP-hydrolysis motif for inflammasome inhibition", Nat. Chem. Biol. 15, 556–559 (2019).

[3]. Stancu, I.-C. et al, "Aggregated Tau activates NLRP3–ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo", Acta Neuropathol. (Berl.) 137, 599–617 (2019).

[4]. Qi, Y., Klyubin, I., Ondrejcak, T., Hu, N.-W. and Rowan, M. J., "Enduring glucocorticoid-evoked exacerbation of synaptic plasticity disruption in male rats modelling early Alzheimer’s disease amyloidosis," Neuropsychopharmacology 46, 2170–2179 (2021).

[5]. Jia, L. et al, " Inhibition of NLRP3 alleviated chemotherapy-induced cognitive impairment in rats," Neurosci. Lett. 793, 136975 (2023).

[6]. Lonnemann, N. et al, "The NLRP3 inflammasome inhibitor OLT1177 rescues cognitive impairment in a mouse model of Alzheimer’s disease", Proc. Natl. Acad. Sci. U. S. A. 117, 32145–32154 (2020).

[7]. Haneklaus, M. et al, "Cutting edge: miR-223 and EBV miR-BART15 regulate the NLRP3 inflammasome and IL-1β production," J. Immunol. Baltim. Md 1950 189, 3795–3799 (2012).

[8]. Campani, V. et al, "Hybrid lipid self-assembling nanoparticles for brain delivery of microRNA", Int. J. Pharm. 588, 119693 (2020).

[9]. Mancuso, R. et al, " Circulatory miR-223-3p Discriminates Between Parkinson's and Alzheimer's Patients", Sci Rep. 28, 9(1), 9393 (2019)

[10]. de Rivero Vaccari, J. P. et al, "Mechanism action of IC 100, a humanized IgG4 monoclonal antibody targeting apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)", Transl Res. 251, 27–40 (2023).

[11]. Dick, M., Sborgi, L., Rühl, S., Hiller, S. and Broz, P, "ASC filament formation serves as a signal amplification mechanism for inflammasomes", Nat. Commun. 7, 11929 (2016).

[12]. Vontell, R. T. et al, "Identification of inflammasome signaling proteins in neurons and microglia in early and intermediate stages of Alzheimer’s disease", Brain Pathol. Zurich Switz. e13142 (2022).

[13]. Kang, J.-H. et al, "Novel Activity of ODZ10117, a STAT3 Inhibitor, for Regulation of NLRP3 Inflammasome Activation", Int. J. Mol. Sci. 24, 6079 (2023).

[14]. He, Y., Zeng, M. Y., Yang, D., Motro, B. and Núñez, G, "NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux", Nature 530, 354–357 (2016).

[15]. Jang, A.-R., Lee, H.-N., Hong, J. J., Kim, Y.-M. Park, J.-H., "Ethanol extract of Chrysanthemum zawadskii inhibits the NLRP3 inflammasome by suppressing ASC oligomerization in macrophages", Exp. Ther. Med. 25, 128 (2023).

[16]. Jayabalan, N. et al, "A Review of RRx-001: A Late-Stage Multi-Indication Inhibitor of NLRP3 Activation and Chronic Inflammation", Drugs 83, 389–402 (2023).

[17]. Reid, T., Oronsky, B., Caroen, S. and Cabrales, P., "The direct NLRP3 inhibitor and Phase 3 small molecule anticancer agent, RRx-001, protects aged triple transgenic Alzheimer’s disease model mice from CNS degeneration and cognitive decline", Alzheimers Dement. 18, e061516 (2022).

[18]. Youm, Y.-H. et al, "The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome–mediated inflammatory disease", Nat. Med. 21, 263–269 (2015).

[19]. Shippy, D.-C. et al, " β-Hydroxybutyrate inhibits inflammasome activation to attenuate Alzheimer’s disease pathology", J. Neuroinflammation 21;17(1):280 (2020)

[20]. Kuwar, R. et al, "A Novel Inhibitor Targeting NLRP3 Inflammasome Reduces Neuropathology and Improves Cognitive Function in Alzheimer’s Disease Transgenic Mice", J. Alzheimers Dis. 82, 1769–1783 (2021).

[21]. Zhang, C. et al, "Targeting NLRP3 signaling by a novel-designed sulfonylurea compound for inhibition of microglial inflammation", Bioorg. Med. Chem. 58, 116645 (2022).

[22]. Wang, B. et al, "Structural Proteomic Profiling of Cerebrospinal Fluids to Reveal Novel Conformational Biomarkers for Alzheimer’s Disease", J. Am. Soc. Mass Spectrom. 34, 459–471 (2023).

[23]. Mu, X. et al, "A novel label-free universal biosensing platform based on CRISPR/Cas12a for biomarker detection", Talanta 251, 123795 (2023).