Targeting ceramide-induced microglial pyroptosis: Icariin is a promising therapy for Alzheimer's disease

Hongli Li; Qiao Xiao; Lemei Zhu; Jin Kang; Qiong Zhan; Weijun Peng

doi:10.1016/j.jpha.2024.101106

Volume 15 Issue 4

May 2025

Turn off MathJax

Article Contents

Article Navigation > Journal of Pharmaceutical Analysis > 2025 > 15(4): 101106

Hongli Li, Qiao Xiao, Lemei Zhu, Jin Kang, Qiong Zhan, Weijun Peng. Targeting ceramide-induced microglial pyroptosis: Icariin is a promising therapy for Alzheimer's disease[J]. Journal of Pharmaceutical Analysis, 2025, 15(4): 101106. doi: 10.1016/j.jpha.2024.101106

Citation:

Hongli Li, Qiao Xiao, Lemei Zhu, Jin Kang, Qiong Zhan, Weijun Peng. Targeting ceramide-induced microglial pyroptosis: Icariin is a promising therapy for Alzheimer's disease[J]. Journal of Pharmaceutical Analysis, 2025, 15(4): 101106. doi: 10.1016/j.jpha.2024.101106

Citation:

Hongli Li, Qiao Xiao, Lemei Zhu, Jin Kang, Qiong Zhan, Weijun Peng. Targeting ceramide-induced microglial pyroptosis: Icariin is a promising therapy for Alzheimer's disease[J]. Journal of Pharmaceutical Analysis, 2025, 15(4): 101106. doi: 10.1016/j.jpha.2024.101106

PDF( 9943 KB)

Targeting ceramide-induced microglial pyroptosis: Icariin is a promising therapy for Alzheimer's disease

doi: 10.1016/j.jpha.2024.101106

Hongli Li^a,b,
Qiao Xiao^a,b,
Lemei Zhu^a,b,
Jin Kang^c,
Qiong Zhan^{d,e
,
,},
Weijun Peng^{a,b
,
,}

a. Department of Integrated Traditional Chinese & Western Medicine, The Second Xiangya Hospital of Central South University, Changsha, 410011, China;
b. National Clinical Research Center for Metabolic Diseases, Changsha, 410011, China;
c. Department of Rheumatology and Immunology, The Second Xiangya Hospital of Central South University, Changsha, 410011, China;
d. Department of Neurology, The Second Xiangya Hospital of Central South University, Changsha, 410011, China;
e. Clinical Medical Research Center for Stroke Prevention and Treatment of Hunan Province, Department of Neurology, The Second Xiangya Hospital of Central South University, Changsha, 410011, China

Funds:

This work was financially supported by the National Natural Science Foundation of China (Grant No.: 82374552), Hunan Provincial Natural Science Foundation of China for Distinguished Young Scholars (Grant No.: 2024JJ2086), the Science and Technology Innovation Program of Hunan Province, China (Grant No.: 2022RC1220), and Support Plan for High-level Health and Medical Talents in Hunan Province, China.

Received Date: May 16, 2024
Accepted Date: Sep. 13, 2024
Rev Recd Date: Sep. 03, 2024
Publish Date: Sep. 19, 2024

Abstract

Abstract

Alzheimer's disease (AD), a progressive dementia, is one of the most common neurodegenerative diseases. Clinical trial results of amyloid-β (Aβ) and tau regulators based on the pretext of straightforward amyloid and tau immunotherapy were disappointing. There are currently no effective strategies for slowing the progression of AD. Herein, we spotlight the dysregulation of lipid metabolism, particularly the elevation of ceramides (Cers), as a critical yet underexplored facet of AD pathogenesis. Our study delineates the role of Cers in promoting microglial pyroptosis, a form of programmed cell death distinct from apoptosis and necroptosis, characterized by cellular swelling, and membrane rupture mediated by the NLRP3 inflammasome pathway. Utilizing both in vivo experiments with amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice and in vitro assays with BV-2 microglial cells, we investigate the activation of microglial pyroptosis by Cers and its inhibition by icariin (ICA), a flavonoid with known antioxidant and anti-inflammatory properties. Our findings reveal a significant increase in Cers levels and pyroptosis markers (NOD-like receptor family, pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase recruitment domain, caspase-1, gasdermin D (GSDMD), and interleukin-18 (IL-18)) in the brains of AD model mice, indicating a direct involvement of Cers in AD pathology through the induction of microglial pyroptosis. Conversely, ICA treatment effectively reduces these pyroptotic markers and Cer levels, thereby attenuating microglial pyroptosis and suggesting a novel therapeutic mechanism of action against AD. This study not only advances our understanding of the pathogenic role of Cers in AD but also introduces ICA as a promising candidate for AD therapy, capable of mitigating neuroinflammation and pyroptosis through the cyclooxygenase-2 (COX-2)-NLRP3 inflammasome-gasdermin D (GSDMD) axis. Our results pave the way for further exploration of Cer metabolism disorders in neurodegenerative diseases and highlight the therapeutic potential of targeting microglial pyroptosis in AD.
- Alzheimer's disease,
- Ceramides,
- Microglia pyroptosis,
- COX2,
- NLRP3 inflammasome,
- Icariin

FullText(HTML)

References(49)

References

[1]	J. Jia, Y. Ning, M. Chen, et al., Biomarker changes during 20 years preceding Alzheimer's disease, N. Engl. J. Med. 390 (2024) 712-722.
[2]	E.E. Congdon, C. Ji, A.M. Tetlow, et al., Tau-targeting therapies for Alzheimer disease: Current status and future directions, Nat. Rev. Neurol. 19 (2023) 715-736.
[3]	R. Kosoy, J.F. Fullard, B. Zeng, et al., Genetics of the human microglia regulome refines Alzheimer's disease risk loci, Nat. Genet. 54 (2022) 1145-1154.
[4]	D. Singh, Astrocytic and microglial cells as the modulators of neuroinflammation in Alzheimer's disease, J. Neuroinflammation 19 (2022), 206.
[5]	Z. Gao, K. Luo, Y. Hu, et al., Melatonin alleviates chronic stress-induced hippocampal microglia pyroptosis and subsequent depression-like behaviors by inhibiting Cathepsin B/NLRP3 signaling pathway in rats, Transl. Psychiatry 14 (2024), 166.
[6]	Z. Yin, S. Herron, S. Silveira, et al., Identification of a protective microglial state mediated by miR-155 and interferon-γ signaling in a mouse model of Alzheimer's disease, Nat. Neurosci. 26 (2023) 1196-1207.
[7]	Y. Zhou, Y. Zhang, H. Wang, et al., Microglial pyroptosis in hippocampus mediates sevolfurane-induced cognitive impairment in aged mice via ROS-NLRP3 inflammasome pathway, Int. Immunopharm. 116 (2023), 109725.
[8]	G. Jing, J. Zuo, Q. Fang, et al., Erbin protects against sepsis-associated encephalopathy by attenuating microglia pyroptosis via IRE1α/Xbp1s-Ca2+ axis, J. Neuroinflammation 19 (2022), 237.
[9]	X. Huang, C. Ye, X. Zhao, et al., TRIM45 aggravates microglia pyroptosis via Atg 5/NLRP3 axis in septic encephalopathy, J. Neuroinflammation 20 (2023), 284.
[10]	S. Moonen, M.J. Koper, E. Van Schoor, et al., Pyroptosis in Alzheimer's disease: Cell type-specific activation in microglia, astrocytes and neurons, Acta Neuropathol. 145 (2023) 175-195.
[11]	A.G. York, M.H. Skadow, J. Oh, et al., IL-10 constrains sphingolipid metabolism to limit inflammation, Nature 627 (2024) 628-635.
[12]	S.M. Crivelli, C. Giovagnoni, L. Visseren, et al., Sphingolipids in Alzheimer's disease, how can we target them? Adv. Drug Deliv. Rev. 159 (2020) 214-231.
[13]	L.S. Kalinichenko, E. Gulbins, J. Kornhuber, et al., Sphingolipid control of cognitive functions in health and disease, Prog. Lipid Res. 86 (2022), 101162.
[14]	M. Yi, C. Zhang, Z. Zhang, et al., Integrated metabolomic and lipidomic analysis reveals the neuroprotective mechanisms of Bushen Tiansui formula in an A β 1-42-induced rat model of Alzheimer's disease, Oxid. Med. Cell. Longev. 2020 (2020), 5243453.
[15]	H. Scheiblich, A. Schlutter, D.T. Golenbock, et al., Activation of the NLRP3 inflammasome in microglia: The role of ceramide, J. Neurochem. 143 (2017) 534-550.
[16]	M. Gaggini, R. Ndreu, E. Michelucci, et al., Ceramides as mediators of oxidative stress and inflammation in cardiometabolic disease, Int. J. Mol. Sci. 23 (2022), 2719.
[17]	L. Su, Y. Chen, C. Huang, et al., Targeting Src reactivates pyroptosis to reverse chemoresistance in lung and pancreatic cancer models, Sci. Transl. Med. 15 (2023), eabl7895.
[18]	F. Liu, Y. Zhang, Y. Shi, et al., Ceramide induces pyroptosis through TXNIP/NLRP3/GSDMD pathway in HUVECs, BMC Mol. Cell Biol. 23 (2022), 54.
[19]	G. Wang, X. Li, N. Li, et al., Icariin alleviates uveitis by targeting peroxiredoxin 3 to modulate retinal microglia M1/M2 phenotypic polarization, Redox Biol. 52 (2022), 102297.
[20]	Y. Liu, H. Li, X. Wang, et al., Anti-Alzheimers molecular mechanism of icariin: Insights from gut microbiota, metabolomics, and network pharmacology, J. Transl. Med. 21 (2023), 277.
[21]	Y. Wang, T. Zhu, M. Wang, et al., Icariin attenuates M1 activation of microglia and aβ plaque accumulation in the hippocampus and prefrontal cortex by up-regulating PPARγ in restraint/isolation-stressed APP/PS1 mice, Front. Neurosci. 13 (2019), 291.
[22]	L. Zhang, R. Song, Y. Shan, et al., Effects of icariin on cognitive function and astrocytic pyroptosis in hemorrhagic shock resuscitation model mice, Chin. J. Behav. Med. ＆ Brain Sci. (2023) 104-110.
[23]	Y. Zu, Y. Mu, Q. Li, et al., Icariin alleviates osteoarthritis by inhibiting NLRP3-mediated pyroptosis, J. Orthop. Surg. Res. 14 (2019), 307.
[24]	H. Li, Y. Tan, X. Cheng, et al., Untargeted metabolomics analysis of the hippocampus and cerebral cortex identified the neuroprotective mechanisms of Bushen Tiansui formula in an aβ25-35-induced rat model of Alzheimer's disease, Front. Pharmacol. 13 (2022), 990307.
[25]	H. Wang, W. Yang, L. Xu, et al., BV2 membrane-coated PEGylated-liposomes delivered hFGF21 to cortical and hippocampal microglia for Alzheimer's disease therapy, Adv. Healthcare Mater. (2024), e2400125.
[26]	E. Araki, C. Forster, J.M. Dubinsky, et al., Cyclooxygenase-2 inhibitor ns-398 protects neuronal cultures from lipopolysaccharide-induced neurotoxicity, Stroke 32 (2001) 2370-2375.
[27]	T. Joki, O. Heese, D.C. Nikas, et al., Expression of cyclooxygenase 2 (COX-2) in human glioma and in vitro inhibition by a specific COX-2 inhibitor, NS-398, Cancer Res. 60 (2000) 4926-4931.
[28]	C.S.-C. Biology, S. Abdulla, B. Aevermann, et al., CZ CELLxGENE discover: A single-cell data platform for scalable exploration, analysis and modeling of aggregated data, bioRxiv 2023-10. https://doi.org/10.1101/2023.10.30.563174.
[29]	T. Li, R. Guo, Q. Zong, et al., Application of molecular docking in elaborating molecular mechanisms and interactions of supramolecular cyclodextrin, Carbohydr. Polym. 276 (2022), 118644.
[30]	X. Zhang, W. Liu, J. Zan, et al., Untargeted lipidomics reveals progression of early Alzheimer's disease in APP/PS1 transgenic mice, Sci. Rep. 10 (2020), 14509.
[31]	Y. Zhang, J. Zhang, Y. Zhao, et al., ChemR23 activation attenuates cognitive impairment in chronic cerebral hypoperfusion by inhibiting NLRP3 inflammasome-induced neuronal pyroptosis, Cell Death Dis. 14 (2023), 721.
[32]	J. Zhou, J. Qiu, Y. Song, et al., Pyroptosis and degenerative diseases of the elderly, Cell Death Dis. 14 (2023), 94.
[33]	Y. Huang, W. Xu, R. Zhou, NLRP3 inflammasome activation and cell death, Cell. Mol. Immunol. 18 (2021) 2114-2127.
[34]	A. Litvinchuk, J.H. Suh, J.L. Guo, et al., Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegeneration with an LXR agonist, Neuron 112 (2024), 2079.
[35]	C. Han, Y. Yang, Q. Guan, et al., New mechanism of nerve injury in Alzheimer's disease: β-amyloid-induced neuronal pyroptosis, J. Cell Mol. Med. 24 (2020) 8078-8090.
[36]	W. Hong, C. Hu, C. Wang, et al., Effects of amyloid β (Aβ)42 and Gasdermin D on the progression of Alzheimer's disease in vitro and in vivo through the regulation of astrocyte pyroptosis, Aging 15 (2023) 12209-12224.
[37]	C. Tallon, B.J. Bell, M.M. Malvankar, et al., Inhibiting tau-induced elevated nSMase 2 activity and ceramides is therapeutic in an Alzheimer's disease mouse model, Transl. Neurodegener. 12 (2023), 56.
[38]	R.G. Cutler, J. Kelly, K. Storie, et al., Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease, Proc. Natl. Acad. Sci. USA 101 (2004) 2070-2075.
[39]	N.M. de Wit, S. den Hoedt, P. Martinez-Martinez, et al., Astrocytic ceramide as possible indicator of neuroinflammation, J. Neuroinflammation 16 (2019), 48.
[40]	A. Elsherbini, A.S. Kirov, M.B. Dinkins, et al., Association of Aβ with ceramide-enriched astrosomes mediates Aβ neurotoxicity, Acta Neuropathol. Commun. 8 (2020), 60.
[41]	L.M. Pujol-Lereis, Alteration of sphingolipids in biofluids: Implications for neurodegenerative diseases, Int. J. Mol. Sci. 20 (2019), 3564.
[42]	S.H. Park, J. Park, M. Lee, et al., Wheat ceramide powder mitigates ultraviolet B-induced oxidative stress and photoaging by inhibiting collagen proteolysis and promoting collagen synthesis in hairless mice, Prev. Nutr. Food Sci. 28 (2023) 418-426.
[43]	L. Zheng, S. Wu, H. Jin, et al., Molecular mechanisms and therapeutic potential of icariin in the treatment of Alzheimer's disease, Phytomed. Int. J. Phytother. Phytopharm. 116 (2023), 154890.
[44]	Z. Luo, J. Dong, J. Wu, Impact of Icariin and its derivatives on inflammatory diseases and relevant signaling pathways, Int. Immunopharm. 108 (2022), 108861.
[45]	L. Yu, X. Dong, T. Huang, et al., Inhibition of ferroptosis by icariin treatment attenuates excessive ethanol consumption-induced atrial remodeling and susceptibility to atrial fibrillation, role of SIRT1, Apoptosis 28 (2023) 607-626.
[46]	A. Steel, M.M. Billings, E.H. Silson, et al., A network linking scene perception and spatial memory systems in posterior cerebral cortex, Nat. Commun. 12 (2021), 2632.
[47]	M. Stacho, D. Manahan-Vaughan, Mechanistic flexibility of the retrosplenial cortex enables its contribution to spatial cognition, Trends Neurosci. 45 (2022) 284-296.
[48]	K.N.H. Dillen, H.I.L. Jacobs, J. Kukolja, et al., Aberrant functional connectivity differentiates retrosplenial cortex from posterior cingulate cortex in prodromal Alzheimer's disease, Neurobiol. Aging 44 (2016) 114-126.
[49]	C.A. Vasquez-Londono, M.J.R. Howes, G.M. Costa, et al., Scutellaria incarnata Vent. root extract and isolated phenylethanoid glycosides are neuroprotective against C2-ceramide toxicity, J. Ethnopharmacol. 307 (2023), 116218.