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The relevance between abnormally elevated serum ceramide and cognitive impairment in Alzheimer’s disease model mice and its mechanism

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Abstract

Rationale

The plasma ceramide levels in Alzheimer’s disease (AD) patients are found abnormally elevated, which is related to cognitive decline.

Objectives

This research was aimed to investigate the mechanisms of aberrant elevated ceramides in the pathogenesis of AD.

Results

The ICR mice intracerebroventricularly injected with Aβ1-42 and APP/PS1 transgenic mice were employed as AD mice. The cognitive deficiency, impaired episodic and spatial memory were observed without altered spontaneous ability. The serum levels of p-tau and ceramide were evidently elevated. The modified expressions and activities of glycogen synthase kinase-3β (GSK-3β) and protein phosphatase 2A (PP2A) influenced the serum content of p-tau. The levels of ceramide synthesis-related genes including sptlc1, sptlc2, cers2, and cers6 in the liver of AD mice were increased, while the ceramide degradation-related gene asah2 did not significantly change. The regulations of these genes were conducted by activated nuclear factor kappa-B (NF-κB) signaling. NF-κB, promoted by free fatty acid (FFA), also increased the hepatic concentrations of proinflammatory cytokines. The FFA amount was modulated by fatty acid synthesis-related genes acc1 and srebp-1c. Besides, the decreased levels of pre-proopiomelanocortin (pomc) mRNA and increased agouti-related protein (agrp) mRNA were found in the hypothalamus without significant alteration of melanocortin receptor 4 (MC4R) mRNA. The bioinformatic analyses proved the results using GEO datasets and AlzData.

Conclusions

Ceramide was positively related to the increased p-tau and impaired cognitive function. The increased generation of ceramide and endoplasmic reticulum stress in the hypothalamus was positively related to fatty acid synthesis and NF-κB signaling via brain–liver axis.

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References

  • Bailly M, Ribeiro MJ, Vercouillie J, Hommet C, Gissot V, Camus V, Guilloteau D (2015) 18F-FDG and 18F-florbetapir PET in clinical practice: regional analysis in mild cognitive impairment and Alzheimer disease. Clin Nucl Med 40:e111–e116

    Article  PubMed  Google Scholar 

  • Barrier L, Fauconneau B, Noël A, Ingrand S (2010) Ceramide and related-sphingolipid levels are not altered in disease-associated brain regions of APP and APP/PS1 Mouse models of Alzheimer’s disease: relationship with the lack of neurodegeneration? Int J Alzheimers Dis 2011:920958

    PubMed  PubMed Central  Google Scholar 

  • Barthélemy NR, Horie K, Sato C, Bateman RJ (2020) Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer’s disease. J Exp Med 217(11):e20200861

  • Ben-David O, Futerman AH (2010) The role of the ceramide acyl chain length in neurodegeneration: involvement of ceramide synthases. NeuroMol Med 12:341–350

    Article  CAS  Google Scholar 

  • Boden G, She P, Mozzoli M, Cheung P, Gumireddy K, Reddy P, **ang X, Luo Z, Ruderman N (2005) Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-kappaB pathway in rat liver. Diabetes 54:3458–3465

    Article  CAS  PubMed  Google Scholar 

  • Brickman AM, Manly JJ, Honig LS, Sanchez D, Reyes-Dumeyer D, Lantigua RA, Lao PJ, Stern Y, Vonsattel JP, Teich AF, Airey DC, Proctor NK, Dage JL, Mayeux R (2021) Plasma p-tau181, p-tau217, and other blood-based Alzheimer’s disease biomarkers in a multi-ethnic, community study. Alzheimer Dement 17:1353–1364

    Article  CAS  Google Scholar 

  • Cao M, Zhang S, Lam SM, Shui G (2022) Hepatic loss of CerS2 induces cell division defects via a mad2-mediated pathway. Clin Transl Med 12:e712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Castro BM, Prieto M, Silva LC (2014) Ceramide: a simple sphingolipid with unique biophysical properties. Prog Lipid Res 54:53–67

    Article  CAS  PubMed  Google Scholar 

  • Charytoniuk T, Sztolsztener K, Bielawiec P, Chabowski A, Konstantynowicz-Nowicka K, Harasim-Symbor E (2022) Cannabidiol downregulates myocardial de novo ceramide synthesis pathway in a rat model of high-fat diet-induced obesity. Int J Mol Sci 23(4):2232

  • Chen J, Li X, Ma D, Liu T, Tian P, Wu C (2017) Ceramide synthase-4 orchestrates the cell proliferation and tumor growth of liver cancer in vitro and in vivo through the nuclear factor-κB signaling pathway. Oncol Lett 14:1477–1483

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen T, Liu S, Zheng M, Li Y, He L (2021) The effect of geniposide on chronic unpredictable mild stress-induced depressive mice through BTK/TLR4/NF-κB and BDNF/TrkB signaling pathways. Phytotherapy Research : PTR 35:932–945

    Article  CAS  PubMed  Google Scholar 

  • Cheng ZY, Hu YH, **a QP, Wang C, He L (2021) DRD1 agonist A-68930 improves mitochondrial dysfunction and cognitive deficits in a streptozotocin-induced mouse model. Brain Res Bull 175:136–149

    Article  CAS  PubMed  Google Scholar 

  • Contreras C, González-García I, Martínez-Sánchez N, Seoane-Collazo P, Jacas J, Morgan DA, Serra D, Gallego R, Gonzalez F, Casals N, Nogueiras R, Rahmouni K, Diéguez C, López M (2014) Central ceramide-induced hypothalamic lipotoxicity and ER stress regulate energy balance. Cell Rep 9:366–377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Custodia A, Aramburu-Núñez M, Correa-Paz C, Posado-Fernández A, Gómez-Larrauri A, Castillo J, Gómez-Muñoz A, Sobrino T, Ouro A (2021) Ceramide metabolism and Parkinson’s disease-therapeutic targets. Biomolecules 11(7):945

  • Cutler RG, Kelly J, Storie K, Pedersen WA, Tammara A, Hatanpaa K, Troncoso JC, Mattson MP (2004) Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer’s disease. Proc Natl Acad Sci U S A 101:2070–2075

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  • Czubowicz K, Jęśko H, Wencel P, Lukiw WJ, Strosznajder RP (2019) The role of ceramide and sphingosine-1-phosphate in Alzheimer’s disease and other neurodegenerative disorders. Mol Neurobiol 56:5436–5455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de la Monte SM, Tong M, Nguyen V, Setshedi M, Longato L, Wands JR (2010) Ceramide-mediated insulin resistance and impairment of cognitive-motor functions. J Alzheimer Dis : JAD 21:967–984

    Article  PubMed  Google Scholar 

  • den Hoedt S, Crivelli SM, Leijten FPJ, Losen M, Stevens JAA, Mané-Damas M, de Vries HE, Walter J, Mirzaian M, Sijbrands EJG, Aerts J, Verhoeven AJM, Martinez-Martinez P, Mulder MT (2021) Effects of sex, age, and apolipoprotein E genotype on brain ceramides and sphingosine-1-phosphate in Alzheimer’s disease and control mice. Front Aging Neurosci 13:765252

    Article  CAS  Google Scholar 

  • Dinkins MB, Dasgupta S, Wang G, Zhu G, Bieberich E (2014) Exosome reduction in vivo is associated with lower amyloid plaque load in the 5XFAD mouse model of Alzheimer’s disease. Neurobiol Aging 35:1792–1800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Du B, Lian Y, Chen C, Zhang H, Bi Y, Fan C, Bi X (2019) Strong association of serum GSK-3β/BDNF ratio with mild cognitive impairment in elderly type 2 diabetic patients. Curr Alzheimer Res 16:1151–1160

    Article  CAS  PubMed  Google Scholar 

  • Ferreira HB, Melo T, Monteiro A, Paiva A, Domingues P, Domingues MR (2021) Serum phospholipidomics reveals altered lipid profile and promising biomarkers in multiple sclerosis. Arch Biochem Biophys 697:108672

    Article  CAS  PubMed  Google Scholar 

  • Gandy JC, Melendez-Ferro M, Bijur GN, Van Leuven F, Roche JK, Lechat B, Devijver H, Demedts D, Perez-Costas E, Roberts RC (2013) Glycogen synthase kinase-3β (GSK3β) expression in a mouse model of Alzheimer’s disease: a light and electron microscopy study. Synapse (new York, NY) 67:313–327

    Article  CAS  Google Scholar 

  • Gautheron V, Auffret A, Mattson MP, Mariani J, Vernet-der Garabedian B (2009) A new and simple approach for genoty** Alzheimer’s disease presenilin-1 mutant knock-in mice. J Neurosci Methods 181:235–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Graff-Radford J, Yong KXX, Apostolova LG, Bouwman FH, Carrillo M, Dickerson BC, Rabinovici GD, Schott JM, Jones DT, Murray ME (2021) New insights into atypical Alzheimer’s disease in the era of biomarkers. Lancet Neurol 20:222–234

    Article  PubMed  PubMed Central  Google Scholar 

  • Gyte A, Pritchard LE, Jones HB, Brennand JC, White A (2007) Reduced expression of the KATP channel subunit, Kir6.2, is associated with decreased expression of neuropeptide Y and agouti-related protein in the hypothalami of Zucker diabetic fatty rats. J Neuroendocrinol 19:941–951

    Article  CAS  PubMed  Google Scholar 

  • Hallett PJ, Huebecker M, Brekk OR, Moloney EB, Rocha EM, Priestman DA, Platt FM, Isacson O (2018) Glycosphingolipid levels and glucocerebrosidase activity are altered in normal aging of the mouse brain. Neurobiol Aging 67:189–200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hammerschmidt P, Ostkotte D, Nolte H, Gerl MJ, Jais A, Brunner HL, Sprenger HG, Awazawa M, Nicholls HT, Turpin-Nolan SM, Langer T, Krüger M, Brügger B, Brüning JC (2019) CerS6-derived sphingolipids interact with Mff and promote mitochondrial fragmentation in obesity. Cell 177:1536-1552.e23

    Article  CAS  PubMed  Google Scholar 

  • Holland WL, Bikman BT, Wang LP, Yuguang G, Sargent KM, Bulchand S, Knotts TA, Shui G, Clegg DJ, Wenk MR, Pagliassotti MJ, Scherer PE, Summers SA (2011) Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice. J Clin Invest 121:1858–1870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hong L, Hongmei W, Leijie X, Dandan Z, Peng L, Zhifei H, Ruimin M, Yijun S, Guanghui Z, Guojun Z (2021) Serum ceramide concentrations are associated with depression in patients after ischemic stroke-a two-center case-controlled study. Clinica chimica acta. Int J Clin Chem 518:110–115

    CAS  Google Scholar 

  • Jiang M, Huang S, Duan W, Liu Q, Lei M (2019) Inhibition of acid sphingomyelinase activity ameliorates endothelial dysfunction in db/db mice. Biosci Rep 39(4):BSR20182144

  • Katsel P, Li C, Haroutunian V (2007) Gene expression alterations in the sphingolipid metabolism pathways during progression of dementia and Alzheimer’s disease: a shift toward ceramide accumulation at the earliest recognizable stages of Alzheimer’s disease? Neurochem Res 32:845–856

    Article  CAS  PubMed  Google Scholar 

  • Kim EM, O’Hare E, Grace MK, Welch CC, Billington CJ, Levine AS (2000) ARC POMC mRNA and PVN alpha-MSH are lower in obese relative to lean Zucker rats. Brain Res 862:11–16

    Article  CAS  PubMed  Google Scholar 

  • Lane CA, Hardy J, Schott JM (2018) Alzheimer disease. Eur J Neurol 25(1):59–70

  • Laviad EL, Albee L, Pankova-Kholmyansky I, Epstein S, Park H, Merrill AH Jr, Futerman AH (2008) Characterization of ceramide synthase 2: tissue distribution, substrate specificity, and inhibition by sphingosine 1-phosphate. J Biol Chem 283:5677–5684

    Article  CAS  PubMed  Google Scholar 

  • Leckstrom A, Lew PS, Poritsanos NJ, Mizuno TM (2011) Central melanocortin receptor agonist reduces hepatic lipogenic gene expression in streptozotocin-induced diabetic mice. Life Sci 88:664–669

    Article  CAS  PubMed  Google Scholar 

  • Liu X, Cheng ZY, Li YF, Liu C, Wang C, Gong XJ, He L (2023) Dopamine D2 receptor agonist bromocriptine ameliorates Aβ(1–42)-induced memory deficits and neuroinflammation in mice. Eur J Pharmacol 938:175443

    Article  CAS  PubMed  Google Scholar 

  • McGrath ER, Himali JJ, Xanthakis V, Duncan MS, Schaffer JE, Ory DS, Peterson LR, DeCarli C, Pase MP, Satizabal CL, Vasan RS, Beiser AS, Seshadri S (2020) Circulating ceramide ratios and risk of vascular brain aging and dementia. Ann Clin Transl Neurol 7:160–168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mielke MM, Bandaru VV, Haughey NJ, **a J, Fried LP, Yasar S, Albert M, Varma V, Harris G, Schneider EB, Rabins PV, Bandeen-Roche K, Lyketsos CG, Carlson MC (2012) Serum ceramides increase the risk of Alzheimer disease: the Women’s Health and Aging Study II. Neurology 79:633–641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Palmqvist S, Janelidze S, Quiroz YT, Zetterberg H, Lopera F, Stomrud E, Su Y, Chen Y, Serrano GE, Leuzy A, Mattsson-Carlgren N, Strandberg O, Smith R, Villegas A, Sepulveda-Falla D, Chai X, Proctor NK, Beach TG, Blennow K, Dage JL, Reiman EM, Hansson O (2020) Discriminative accuracy of plasma phospho-tau217 for Alzheimer disease vs other neurodegenerative disorders. JAMA 324:772–781

    Article  CAS  PubMed  Google Scholar 

  • Park JC, Han SH, Yi D, Byun MS, Lee JH, Jang S, Ko K, Jeon SY, Lee YS, Kim YK, Lee DY, Mook-Jung I (2019) Plasma tau/amyloid-β1-42 ratio predicts brain tau deposition and neurodegeneration in Alzheimer’s disease. Brain 142:771–786

    Article  PubMed  Google Scholar 

  • Park WJ, Song JH, Kim GT, Park TS (2020) Ceramide and sphingosine 1-phosphate in liver diseases. Mol Cells 43:419–430

    CAS  PubMed  PubMed Central  Google Scholar 

  • Porter WD, Flatt PR, Hölscher C, Gault VA (2013) Liraglutide improves hippocampal synaptic plasticity associated with increased expression of Mash1 in ob/ob mice. Int J Obes 37:678–684

  • Raichur S, Brunner B, Bielohuby M, Hansen G, Pfenninger A, Wang B, Bruning JC, Larsen PJ, Tennagels N (2019) The role of C16:0 ceramide in the development of obesity and type 2 diabetes: CerS6 inhibition as a novel therapeutic approach. Mol Metab 21:36–50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shieh JC, Huang PT, Lin YF (2020) Alzheimer’s disease and diabetes: insulin signaling as the bridge linking two pathologies. Mol Neurobiol 57:1966–1977

    Article  CAS  PubMed  Google Scholar 

  • Strom A, Iaccarino L, Edwards L, Lesman-Segev OH, Soleimani-Meigooni DN, Pham J, Baker SL, Landau SM, Jagust WJ, Miller BL, Rosen HJ, Gorno-Tempini ML, Rabinovici GD, La Joie R (2022) Cortical hypometabolism reflects local atrophy and tau pathology in symptomatic Alzheimer’s disease. Brain 145:713–728

    Article  PubMed  Google Scholar 

  • Svennerholm L (1994) Gangliosides–a new therapeutic agent against stroke and Alzheimer’s disease. Life Sci 55:2125–2134

    Article  CAS  PubMed  Google Scholar 

  • Thota RN, Rosato JI, Dias CB, Burrows TL, Martins RN, Garg ML (2020) Dietary supplementation with curcumin reduce circulating levels of glycogen synthase kinase-3β and islet amyloid polypeptide in adults with high risk of type 2 diabetes and Alzheimer’s disease. Nutrients 12(4):1032

  • Wang G, Silva J, Dasgupta S, Bieberich E (2008) Long-chain ceramide is elevated in presenilin 1 (PS1M146V) mouse brain and induces apoptosis in PS1 astrocytes. Glia 56:449–456

    Article  PubMed  Google Scholar 

  • Watt MJ, Barnett AC, Bruce CR, Schenk S, Horowitz JF, Hoy AJ (2012) Regulation of plasma ceramide levels with fatty acid oversupply: evidence that the liver detects and secretes de novo synthesised ceramide. Diabetologia 55:2741–2746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xu M, Zhang DF, Luo R, Wu Y, Zhou H, Kong LL, Bi R, Yao YG (2018) A systematic integrated analysis of brain expression profiles reveals YAP1 and other prioritized hub genes as important upstream regulators in Alzheimer’s disease. Alzheimer Dement 14:215–229

    Article  Google Scholar 

  • Yang W, Liu Y, Xu QQ, **an YF, Lin ZX (2020) Sulforaphene ameliorates neuroinflammation and hyperphosphorylated tau protein via regulating the PI3K/Akt/GSK-3β pathway in experimental models of Alzheimer’s disease. Oxid Med Cell Longev 2020:4754195

    Article  PubMed  PubMed Central  Google Scholar 

  • Zelnik ID, Rozman B, Rosenfeld-Gur E, Ben-Dor S, Futerman AH (2019) A stroll down the CerS lane. Adv Exp Med Biol 1159:49–63

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China (82003968 for Tong Chen, No. 81673434 for Ling He) and the “Double First-Class” University project (CPU2018GY22 for Ling He).

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  1. **n Liu and Yongzeng ** contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, China Pharmaceutical University, Nan**g, China

    **n Liu, Yongzeng **, **nyi Cheng, Qinghua Song, Yanan Wang, Ling He & Tong Chen

  2. School of Medicine, Tongji University, Shanghai, 200092, China

    **n Liu

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  1. **n Liu
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  2. Yongzeng **
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  3. **nyi Cheng
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  4. Qinghua Song
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  6. Ling He
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  7. Tong Chen
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Correspondence to Ling He or Tong Chen.

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Liu, X., **, Y., Cheng, X. et al. The relevance between abnormally elevated serum ceramide and cognitive impairment in Alzheimer’s disease model mice and its mechanism. Psychopharmacology 241, 525–542 (2024). https://doi.org/10.1007/s00213-024-06530-y

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