eISSN: 1509-572x
ISSN: 1641-4640
Folia Neuropathologica
Current issue Archive Manuscripts accepted About the journal Abstracting and indexing Subscription Contact Instructions for authors
SCImago Journal & Country Rank
vol. 56
Original paper

The role of ceramide and SEW 2871 in the transcription of enzymes involved in amyloid b precursor protein metabolism in an experimental model of Alzheimer’s disease

Kinga Czubowicz, Sylwia Wójtowicz, Przemysław Leonard Wencel, Robert Piotr Strosznajder

Folia Neuropathol 2018; 56 (3): 196-205
Online publish date: 2018/09/28
View full text
Get citation
JabRef, Mendeley
Papers, Reference Manager, RefWorks, Zotero
Alzheimer’s disease (AD) is characterized by alterations of amyloid precursor protein (APP) metabolism, accumulation of amyloid  peptides (A), hyperphosphorylation of Tau proteins and also by sphingolipids disturbances. These changes lead to oxidative stress, mitochondria dysfunction, synaptic loss and neuro-inflammation. It is known that A may promote ceramides formation and reversely, ceramides could stimulate A peptides release. However, the effect of ceramide and sphingosine-1-phosphate (S1P) on APP metabolism has not been fully elucidated. In this study we investigated the role of ceramide and S1P on APP metabolism. Moreover, the effect of ceramide and SEW 2871 (agonist for S1P receptor-1) on Sirt1 (NAD+-dependent nuclear enzyme responsible for stress response) gene expression under A toxicity was analyzed. Experiments were carried out using pheochromocytoma cells (PC-12) transfected with: an empty vector (used as a control), human wild-type APP gene (APPwt) and Swedish mutated (K670M/N671L) APP gene (APPsw). Our results indicated that C2-ceramide significantly decreased the viability of the APPwt, APPsw as well as empty vector-transfected PC12 cells. It was observed that C2-ceramide had no significant effect on the mRNA level of - and -secretase in APPwt and APPsw cells. However, it significantly decreased transcription of -secretase in control cells. Results also showed a significant increase in Psen1 (crucial subunit of -secretase) gene expression in APPsw cells after incubation with C2-ceramide. We observed that SEW 2871 significantly upregulated the mRNA level of -secretase in control-empty vector-transfected cells subjected to C2-ceramide toxicity. The same tendency, though insignificant, was observed in APPwt and APPsw cells. Moreover, SEW 2871 enhanced the mRNA level of -secretase and Psen1 in APPsw cells after C2-ceramide treatment. Additionally, SEW 2871 significantly upregulated a gene expression of Sirt1 in APPwt and also APPsw cells subjected to C2-ceramide toxicity. Furthermore, it was observed that SEW 2871 significantly enhanced the viability of all investigated cells’ lines probably through its positive influence on Sirt1.

amyloid  peptide, ceramide, sphingosine-1-phosphate, secretases, sirtuins

Allinson TM, Parkin ET, Turner AJ, Hooper NM. ADAMs family members as amyloid precursor protein -secretases. J Neurosci Res 2003; 74: 342-352.
Arboleda G, Cárdenas Y, Rodríguez Y, Morales LC, Matheus L, Arboleda H. Differential regulation of AKT, MAPK and GSK3 during C2-ceramide-induced neuronal death. Neurotoxicology 2010; 31: 687-693.
Butterfield DA, Swomley AM, Sultana R. Amyloid -peptide (1-42)-induced oxidative stress in Alzheimer disease: importance in disease pathogenesis and progression. Antioxid Redox Signal 2013; 19: 823-835.
Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL, Wong PC. BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat Neurosci 2001; 4: 233-234.
Cao L, Liu C, Wang F, Wang H. SIRT1 negatively regulates amyloid-beta-induced inflammation via the NF-kappaB pathway. Braz J Med Biol Res 2013; 46: 659-669.
Ceccom J, Loukh N, Lauwers-Cances V, Touriol C, Nicaise Y, Gentil C, Uro-Coste E, Pitson S, Maurage CA, Duyckaerts C, Cuvillier O, Delisle M-B. Reduced sphingosine kinase-1 and enhanced sphingosine 1-phosphate lyase expression demonstrate deregulated sphingosine 1-phosphate signaling in Alzheimer’s disease. Acta Neuropathol Commun 2014; 2: 12.
Chakrabarti SS, Bir A, Poddar J, Sinha M, Ganguly A, Chakrabarti S. Ceramide and sphingosine-1-phosphate in cell death pathways: relevance to the pathogenesis of Alzheimer’s disease. Curr Alzheimer Res 2016; 13: 1232-1248.
Chen J, Zhou Y, Mueller-Steiner S, Chen LF, Kwon H, Yi S, Mucke L, Gan L. SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling. J Biol Chem 2005; 280: 40364-40374.
Cieslik M, Czapski GA, Strosznajder JB. The molecular mechanism of amyloid beta42 peptide toxicity: the role of sphingosine kinase-1 and mitochondrial sirtuins. PLoS One 2015; 10: e0137193.
Cutler RG, Kelly J, Storie K, Pedersen WA, Tammara A, Hatanpaa K, Troncoso JC, Mattson MP. 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 2004; 101: 2070-2075.
Czubowicz K, Strosznajder R. Ceramide in the molecular mechanisms of neuronal cell death. The role of sphingosine-1-phosphate. Mol Neurobiol 2014; 50: 26-37.
Filippov V, Song MA, Zhang K, Vinters HV, Tung S, Kirsch WM, Yang J, Duerksen-Hughes PJ. Increased ceramide in brains with Alzheimer’s and other neurodegenerative diseases. J Alzheimer’s Dis 2012; 29: 537-547.
Gao Z, Wang H, Xiao F-J, Shi X-F, Zhang Y-K, Xu QQ, Zhang X-Y, Ha X-Q, Wang L-S. SIRT1 mediates Sphk1/S1P-induced proliferation and migration of endothelial cells. Int J Biochem Cell Biol 2016; 74: 152-160.
Godoy JA, Zolezzi JM, Braidy N, Inestrosa NC. Role of Sirt1 during the ageing process: relevance to protection of synapses in the brain. Mol Neurobiol 2014; 50: 744-756.
Hannun YA, Obeid LM. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 2008; 9: 139-150.
Haughey NJ, Bandaru VV, Bae M, Mattson MP. Roles for dysfunctional sphingolipid metabolism in Alzheimer’s disease neuropathogenesis. Biochim Biophys Acta 2010; 1801: 878-886.
Hirata N, Yamada S, Shoda T, Kurihara M, Sekino Y, Kanda Y. Sphingosine-1-phosphate promotes expansion of cancer stem cells via S1PR3 by a ligand-independent Notch activation. Nat Commun 2014; 5: 4806.
Jana A, Pahan K. Fibrillar amyloid-β-activated human astroglia kill primary human neurons via neutral sphingomyelinase: implications for Alzheimer’s disease. J Neurosci 2010; 30: 12676-12689.
Jazvinscak Jembrek M, Hof PR, Simic G. Ceramides in Alzheimer’s disease: key mediators of neuronal apoptosis induced by oxidative stress and Abeta accumulation. Oxid Med Cell Longev 2015; 2015: 346783.
Jęśko H, Strosznajder RP. Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases. Folia Neuropathol 2016; 3: 212-233.
Jęśko H, Wencel P, Strosznajder RP, Strosznajder JB. Sirtuins and their roles in brain aging and neurodegenerative disorders. Neurochem Res 2017; 42: 876-890.
Julien C, Tremblay C, Emond V, Lebbadi M, Salem N Jr, Bennett DA, Calon F. Sirtuin 1 reduction parallels the accumulation of tau in Alzheimer disease. J Neuropathol Exp Neurol 2009; 68: 48-58.
Kitatani K, Idkowiak-Baldys J, Hannun YA. The sphingolipid salvage pathway in ceramide metabolism and signaling. Cell Signal 2008; 20: 1010-1018.
Kurano M, Hara M, Nojiri T, Ikeda H, Tsukamoto K, Yatomi Y. Resveratrol exerts a biphasic effect on apolipoprotein M. Br J Pharmacol 2016; 173: 222-233.
Lalla R, Donmez G. The role of sirtuins in Alzheimer’s disease. Front Aging Neurosci 2013; 5: 16.
Larson ME, Lesne SE. Soluble Abeta oligomer production and toxicity. J Neurochem 2012; 120 Suppl 1: 125-139.
Lee HR, Shin HK, Park SY, Kim HY, Lee WS, Rhim BY, Hong KW, Kim CD. Cilostazol suppresses beta-amyloid production by activating a disintegrin and metalloproteinase 10 via the upregulation of SIRT1-coupled retinoic acid receptor-beta. J Neurosci Res 2014; 92: 1581-1590.
Lee J-T, Xu J, Lee J-M, Ku G, Han X, Yang D-I, Chen S, Hsu CY. Amyloid- peptide induces oligodendrocyte death by activating the neutral sphingomyelinase-ceramide pathway. J Cell Biol 2004; 164: 123-131.
Lutz MI, Milenkovic I, Regelsberger G, Kovacs GG. Distinct patterns of sirtuin expression during progression of Alzheimer’s disease. Neuromolecular Med 2014; 16: 405-414.
Maceyka M, Harikumar KB, Milstien S, Spiegel S. Sphingo­sine-1-phosphate signaling and its role in disease. Trends Cell Biol 2012; 22: 50-60.
Malaplate-Armand C, Florent-Bechard S, Youssef I. Soluble oligomers of amyloid-beta peptide induce neuronal apoptosis by activating a cPLA2-dependent sphingomyelinase-ceramide pathway. Neurobiol Dis 2006; 23: 178-189.
Marwarha G, Raza S, Meiers C, Ghribi O. Leptin attenuates BACE1 expression and amyloid-beta genesis via the activation of SIRT1 signaling pathway. Biochim Biophys Acta 2014; 1842: 1587-1595.
Mencarelli C, Martinez-Martinez P. Ceramide function in the brain: when a slight tilt is enough. Cell Mol Life Sci 2013; 70: 181-203.
Mielke MM, Haughey NJ, Bandaru VV, Schech S, Carrick R, Carlson MC, Mori S, Miller MI, Ceritoglu C, Brown T, Albert M, Lyketsos CG. Plasma ceramides are altered in mild cognitive impairment and predict cognitive decline and hippocampal volume loss. Alzheimers Dement 2010; 6: 378-385.
Mielke MM, Lyketsos CG. Alterations of the sphingolipid pathway in Alzheimer’s disease: new biomarkers and treatment targets? Neuromolecular Med 2010; 12: 331-340.
Min SW, Cho SH, Zhou Y, Schroeder S, Haroutunian V, Seeley WW,
Huang EJ, Shen Y, Masliah E, Mukherjee C, Meyers D, Cole PA, Ott M, Gan L. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron 2010; 67: 953-966.
Min SW, Sohn PD, Cho SH, Swanson RA, Gan L. Sirtuins in neuro­degenerative diseases: an update on potential mechanisms. Front Aging Neurosci 2013; 5: 53.
Morad SA, Cabot MC. Ceramide-orchestrated signalling in cancer cells. Nat Rev Cancer 2013; 13: 51-65.
Morris BJ. Seven sirtuins for seven deadly diseases ofaging. Free Radic Biol Med 2013; 56: 133-171.
Novgorodov SA, Gudz TI. Ceramide and mitochondria in ische­mia/reperfusion. J Cardiovasc Pharmacol 2009; 53: 198-208.
Olmos Y, Sánchez-Gómez FJ, Wild B, García-Quintans N, Cabezudo S, Lamas S, Monsalve M. SirT1 regulation of antioxidant genes is dependent on the formation of a FoxO3a/PGC-1 complex. Antioxid Redox Signal 2013; 19: 1507-1521.
Olsen ASB, Fćrgeman NJ. Sphingolipids: membrane microdomains in brain development, function and neurological diseases. Open Biol 2017; 7. pii: 170069.
Pajak B, Kania E, Orzechowski A. Nucleofection of rat pheochromocytoma PC-12 cells with human mutated beta-amyloid precursor protein gene (APP-sw) leads to reduced viability, autophagy-like process, and increased expression and secretion of beta amyloid. Biomed Res Int 2015; 2015: 746092.
Panchal M, Gaudin M, Lazar AN, Salvati E, Rivals I, Ayciriex S, Dauphinot L, Dargère D, Auzeil N, Masserini M, Laprévote O, Duyckaerts C. Ceramides and sphingomyelinases in senile plaques. Neurobiol Dis 2014; 65: 193-201.
Park JH, Schuchman EH. Acid ceramidase and human disease. Biochim Biophys Acta 2006; 1758: 2133-2138.
Puglielli L, Ellis BC, Saunders AJ, Kovacs DM. Ceramide stabilizes beta-site amyloid precursor protein-cleaving enzyme 1 and promotes amyloid beta-peptide biogenesis. J Biol Chem 2003; 278: 19777-19783.
Ren Y, Du C, Shi Y, Wei J, Wu H, Cui H. The Sirt1 activator, SRT1720, attenuates renal fibrosis by inhibiting CTGF and oxidative stress. Int J Mol Med 2017; 39: 1317-1324.
Sanchez T, Hla T. Structural and functional characteristics of S1P receptors. J Cell Biochem 2004; 92: 913-922.
Satoh A, Imai S-i, Guarente L. The brain, sirtuins, and ageing. Nat Rev Neurosci 2017; 18: 362-374.
Takasugi N, Sasaki T, Shinohara M, Iwatsubo T, Tomita T. Synthetic ceramide analogues increase amyloid-β 42 production by modulating -secretase activity. Biochem Biophys Res Commun 2015; 457: 194-199.
Takasugi N, Sasaki T, Suzuki K, Osawa S, Isshiki H, Hori Y, Shimada N, Higo T, Yokoshima S, Fukuyama T, Lee VM, Trojanowski JQ, Tomita T, Iwatsubo T. BACE1 activity is modulated by cell-associated sphingosine-1-phosphate. J Neurosci 2011; 31: 6850-6857.
Tamagno E, Guglielmotto M, Aragno M, Borghi R, Autelli R, Giliberto L, Muraca G, Danni O, Zhu X, Smith MA, Perry G, Jo DG, Mattson MP, Tabaton M. Oxidative stress activates a positive feedback between the gamma- and beta-secretase cleavages of the beta-amyloid precursor protein. J Neurochem 2008; 104: 683-695.
Theendakara V, Patent A, Peters Libeu CA, Philpot B, Flores S, Descamps O, Poksay KS, Zhang Q, Cailing G, Hart M, John V, Rao RV, Bredesen DE. Neuroprotective Sirtuin ratio reversed by ApoE4. Proc Natl Acad Sci U S A 2013; 110: 18303-18308.
van Echten-Deckert G, Walter J. Sphingolipids: critical players in Alzheimer’s disease. Prog Lipid Res 2012; 51: 378-393.
Vidaurre OG, Haines JD, Katz Sand I, Adula KP, Huynh JL, Mc­-Graw CA, Zhang F, Varghese M, Sotirchos E, Bhargava P, Bandaru VVR, Pasinetti G, Zhang W, Inglese M, Calabresi PA, Wu G, Miller AE, Haughey NJ, Lublin FD, Casaccia P. Cerebrospinal fluid ceramides from patients with multiple sclerosis impair neuronal bioenergetics. Brain 2014; 137: 2271-2286.
Wang J, Fivecoat H, Ho L, Pan Y, Ling E, Pasinetti GM. The role of Sirt1: At the crossroad between promotion of longevity and protection against Alzheimer’s disease neuropathology. Biochim Biophys Acta 2010; 1804: 1690-1694.
Wang SJ, Zhao XH, Chen W, Bo N, Wang XJ, Chi ZF, Wu W. Sirtuin 1 activation enhances the PGC-1alpha/mitochondrial antioxidant system pathway in status epilepticus. Mol Med Rep 2015; 11: 521-526.
Wencel PL, Lukiw WJ, Strosznajder JB, Strosznajder RP. Inhibition of poly(ADP-ribose) polymerase-1 enhances gene expression of selected sirtuins and APP cleaving enzymes in amyloid beta cytotoxicity. Mol Neurobiol 2018; 55: 4612-4623.
Willaime-Morawek S, Brami-Cherrier K, Mariani J, Caboche J, Brugg B. C-Jun N-terminal kinases/c-Jun and p38 pathways cooperate in ceramide-induced neuronal apoptosis. Neuroscience 2003; 119: 387-397.
Wu F, Schweizer C, Rudinskiy N, Taylor DM, Kazantsev A, Luthi-Carter R, Fraering PC. Novel gamma-secretase inhibitors uncover a common nucleotide-binding site in JAK3, SIRT2, and PS1. FASEB J 2010; 24: 2464-2474.
Xing Y, Tang Y, Zhao L, Wang Q, Qin W, Zhang JL, Jia J. Plasma ceramides and neuropsychiatric symptoms of Alzheimer’s disease. J Alzheimers Dis 2016; 52: 1029-1035.
Zhao Y, Bhattacharjee S, Jones BM, Hill JM, Clement C, Samba­murti K, Dua P, Lukiw WJ. Beta-amyloid precursor protein (betaAPP) processing in Alzheimer’s disease (AD) and age-related macular degeneration (AMD). Mol Neurobiol 2015; 52: 533-544.
Quick links
© 2019 Termedia Sp. z o.o. All rights reserved.
Developed by Bentus.
PayU - płatności internetowe