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Neutral Sphingomyelinase 2 Mediates Oxidative Stress Effects on Astrocyte Senescence and Synaptic Plasticity Transcripts

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Abstract

We have shown that deficiency of neutral sphingomyelinase 2 (nSMase2), an enzyme generating the sphingolipid ceramide, improves memory in adult mice. Here, we performed sphingolipid and RNA-seq analyses on the cortex from 10-month-old nSMase2-deficient (fro/fro) and heterozygous (+ /fro) mice. fro/fro cortex showed reduced levels of ceramide, particularly in astrocytes. Differentially abundant transcripts included several functionally related groups, with decreases in mitochondrial oxidative phosphorylation and astrocyte activation transcripts, while axon guidance and synaptic transmission and plasticity transcripts were increased, indicating a role of nSMase2 in oxidative stress, astrocyte activation, and cognition. Experimentally induced oxidative stress decreased the level of glutathione (GSH), an endogenous inhibitor of nSMase2, and increased immunolabeling for ceramide in primary + /fro astrocytes, but not in fro/fro astrocytes. β-galactosidase activity was lower in 5-week-old fro/fro astrocytes, indicating delayed senescence due to nSMase2 deficiency. In fro/fro cortex, levels of the senescence markers C3b and p27 and the proinflammatory cytokines interleukin 1β, interleukin 6, and tumor necrosis factor α were reduced, concurrent with twofold decreased phosphorylation of their downstream target, protein kinase Stat3. RNA and protein levels of the ionotropic glutamate receptor subunit 2B (Grin2b/NR2B) were increased by twofold, which was previously shown to enhance cognition. This was consistent with threefold reduced levels of exosomes carrying miR-223-3p, a micro-RNA downregulating NR2B. In summary, our data show that nSMase2 deficiency prevents oxidative stress-induced elevation of ceramide and secretion of exosomes by astrocytes that suppress neuronal function, indicating a role of nSMase2 in the regulation of neuroinflammation and cognition.

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Availability of Data and Materials

The RNA-seq data have been submitted to the Gene Expression Omnibus (GEO) database (accession number GSE179045). The datasets used and/or analyzed during the current study are available from the corresponding author (Erhard.bieberich@uky.edu) on reasonable request.

Code Availability

Not applicable.

Abbreviations

AAAs:

Aging-associated astrosomes

Aβ:

Amyloid beta

AD:

Alzheimer’s disease

β-gal:

β-Galactosisdase

C1q:

Complement factor 1q

Cer:

Ceramide

fro/fro :

nSMase2-deficient

 + /fro :

nSMase2 heterozygous

GSH:

Glutathione

GW:

GW4869

IL-1β:

Interleukin 1β

IL-6:

Interleukin 6

IPA:

Ingenuity Pathway Analysis

KEGG:

Kyoto Encyclopedia of Genes and Genomes

LC–MS/MS:

Liquid chromatography-tandem mass spectrometry

MCB:

Monochlorobimane

NAcCys:

N-acetyl cysteine

NR2B/Grin2b:

Glutamate Ionotropic Receptor NMDA Type Subunit 2B

nSMase2:

Neutral sphingomyelinase 2

ROS:

Reactive oxygen species

tBO2H:

Tertiary butyl hydroperoxide

TNF-α:

Tumor necrosis factor α

WT:

Wild type

References

  1. Singh-Manoux A, Kivimaki M, Glymour MM, Elbaz A, Berr C, Ebmeier KP, Ferrie JE, Dugravot A (2012) Timing of onset of cognitive decline: results from Whitehall II prospective cohort study. BMJ 344:d7622. https://doi.org/10.1136/bmj.d7622

    Article  PubMed  PubMed Central  Google Scholar 

  2. Hajjar I, Hayek SS, Goldstein FC, Martin G, Jones DP, Quyyumi A (2018) Oxidative stress predicts cognitive decline with aging in healthy adults: an observational study. J Neuroinflammation 15(1):17. https://doi.org/10.1186/s12974-017-1026-z

    Article  PubMed  PubMed Central  Google Scholar 

  3. Lee M, Cho T, Jantaratnotai N, Wang YT, McGeer E, McGeer PL (2010) Depletion of GSH in glial cells induces neurotoxicity: relevance to aging and degenerative neurological diseases. FASEB J 24(7):2533–2545. https://doi.org/10.1096/fj.09-149997

    Article  CAS  PubMed  Google Scholar 

  4. de Wit NM, den Hoedt S, Martinez-Martinez P, Rozemuller AJ, Mulder MT, de Vries HE (2019) Astrocytic ceramide as possible indicator of neuroinflammation. J Neuroinflammation 16(1):48. https://doi.org/10.1186/s12974-019-1436-1

    Article  PubMed  PubMed Central  Google Scholar 

  5. Wang G, Dinkins M, He Q, Zhu G, Poirier C, Campbell A, Mayer-Proschel M, Bieberich E (2012) Astrocytes secrete exosomes enriched with proapoptotic ceramide and prostate apoptosis response 4 (PAR-4): potential mechanism of apoptosis induction in Alzheimer disease (AD). J Biol Chem 287(25):21384–21395. https://doi.org/10.1074/jbc.M112.340513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gu L, Huang B, Shen W, Gao L, Ding Z, Wu H, Guo J (2013) Early activation of nSMase2/ceramide pathway in astrocytes is involved in ischemia-associated neuronal damage via inflammation in rat hippocampi. J Neuroinflammation 10:109. https://doi.org/10.1186/1742-2094-10-109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Singh I, Pahan K, Khan M, Singh AK (1998) Cytokine-mediated induction of ceramide production is redox-sensitive. Implications to proinflammatory cytokine-mediated apoptosis in demyelinating diseases. J Biol Chem 273(32):20354–20362

    Article  CAS  PubMed  Google Scholar 

  8. Crivelli SM, Giovagnoni C, Visseren L, Scheithauer AL, de Wit N, den Hoedt S, Losen M, Mulder MT, Walter J, de Vries HE, Bieberich E, Martinez-Martinez P (2020) Sphingolipids in Alzheimer’s disease, how can we target them? Adv Drug Deliv Rev. https://doi.org/10.1016/j.addr.2019.12.003

    Article  PubMed  Google Scholar 

  9. Filippov V, Song MA, Zhang K, Vinters HV, Tung S, Kirsch WM, Yang J, Duerksen-Hughes PJ (2012) Increased ceramide in brains with Alzheimer’s and other neurodegenerative diseases. J Alzheimers Dis 29(3):537–547. https://doi.org/10.3233/JAD-2011-111202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nikolova-Karakashian M, Karakashian A, Rutkute K (2008) Role of neutral sphingomyelinases in aging and inflammation. Subcell Biochem 49:469–486. https://doi.org/10.1007/978-1-4020-8831-5_18

    Article  PubMed  Google Scholar 

  11. Dinkins MB, Enasko J, Hernandez C, Wang G, Kong J, Helwa I, Liu Y, Terry AV Jr, Bieberich E (2016) Neutral sphingomyelinase-2 deficiency ameliorates Alzheimer’s disease pathology and improves cognition in the 5XFAD mouse. J Neurosci 36(33):8653–8667. https://doi.org/10.1523/JNEUROSCI.1429-16.2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Dinkins MB, Dasgupta S, Wang G, Zhu G, He Q, Kong JN, Bieberich E (2015) The 5XFAD mouse model of Alzheimer’s disease exhibits an age-dependent increase in anti-ceramide IgG and exogenous administration of ceramide further increases anti-ceramide titers and amyloid plaque burden. J Alzheimers Dis. https://doi.org/10.3233/JAD-150088

    Article  PubMed  PubMed Central  Google Scholar 

  13. 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(8):1792–1800. https://doi.org/10.1016/j.neurobiolaging.2014.02.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rutkute K, Asmis RH, Nikolova-Karakashian MN (2007) Regulation of neutral sphingomyelinase-2 by GSH: a new insight to the role of oxidative stress in aging-associated inflammation. J Lipid Res 48(11):2443–2452. https://doi.org/10.1194/jlr.M700227-JLR200

    Article  CAS  PubMed  Google Scholar 

  15. Liu B, Hannun YA (1997) Inhibition of the neutral magnesium-dependent sphingomyelinase by glutathione. J Biol Chem 272(26):16281–16287

    Article  CAS  PubMed  Google Scholar 

  16. McBean GJ (2017) Cysteine, Glutathione, and thiol redox balance in astrocytes. Antioxidants (Basel) 6 (3). https://doi.org/10.3390/antiox6030062

  17. Aubin I, Adams CP, Opsahl S, Septier D, Bishop CE, Auge N, Salvayre R, Negre-Salvayre A, Goldberg M, Guenet JL, Poirier C (2005) A deletion in the gene encoding sphingomyelin phosphodiesterase 3 (Smpd3) results in osteogenesis and dentinogenesis imperfecta in the mouse. Nat Genet 37(8):803–805. https://doi.org/10.1038/ng1603

    Article  CAS  PubMed  Google Scholar 

  18. Kong JN, Zhu Z, Itokazu Y, Wang G, Dinkins MB, Zhong L, Lin HP, Elsherbini A, Leanhart S, Jiang X, Qin H, Zhi W, Spassieva SD, Bieberich E (2018) Novel function of ceramide for regulation of mitochondrial ATP release in astrocytes. J Lipid Res 59(3):488–506. https://doi.org/10.1194/jlr.M081877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Adler J, Parmryd I (2013) Colocalization analysis in fluorescence microscopy. Methods Mol Biol 931:97–109. https://doi.org/10.1007/978-1-62703-056-4_5

    Article  CAS  PubMed  Google Scholar 

  20. Adler J, Parmryd I (2010) Quantifying colocalization by correlation: the Pearson correlation coefficient is superior to the Mander’s overlap coefficient. Cytometry A 77(8):733–742. https://doi.org/10.1002/cyto.a.20896

    Article  PubMed  Google Scholar 

  21. Bielawski J, Pierce JS, Snider J, Rembiesa B, Szulc ZM, Bielawska A (2009) Comprehensive quantitative analysis of bioactive sphingolipids by high-performance liquid chromatography-tandem mass spectrometry. Methods Mol Biol 579:443–467. https://doi.org/10.1007/978-1-60761-322-0_22

    Article  CAS  PubMed  Google Scholar 

  22. Bielawski J, Pierce JS, Snider J, Rembiesa B, Szulc ZM, Bielawska A (2010) Sphingolipid analysis by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Adv Exp Med Biol 688:46–59

    Article  CAS  PubMed  Google Scholar 

  23. Elsherbini A, Kirov AS, Dinkins MB, Wang G, Qin H, Zhu Z, Tripathi P, Crivelli SM, Bieberich E (2020) Association of Abeta with ceramide-enriched astrosomes mediates Abeta neurotoxicity. Acta Neuropathol Commun 8(1):60. https://doi.org/10.1186/s40478-020-00931-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Elsherbini A, Qin H, Zhu Z, Tripathi P, Crivelli SM, Bieberich E (2020) In vivo evidence of exosome-mediated Abeta neurotoxicity. Acta Neuropathol Commun 8(1):100. https://doi.org/10.1186/s40478-020-00981-y

    Article  PubMed  PubMed Central  Google Scholar 

  25. Mielke MM, Bandaru VV, Haughey NJ, Rabins PV, Lyketsos CG, Carlson MC (2010) Serum sphingomyelins and ceramides are early predictors of memory impairment. Neurobiol Aging 31(1):17–24. https://doi.org/10.1016/j.neurobiolaging.2008.03.011

    Article  CAS  PubMed  Google Scholar 

  26. Mielke MM, Haughey NJ, Bandaru VV, Schech S, Carrick R, Carlson MC, Mori S, Miller MI, Ceritoglu C, Brown T, Albert M, Lyketsos CG (2010) Plasma ceramides are altered in mild cognitive impairment and predict cognitive decline and hippocampal volume loss. Alzheimers Dement 6(5):378–385. https://doi.org/10.1016/j.jalz.2010.03.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mielke MM, Lyketsos CG (2010) Alterations of the sphingolipid pathway in Alzheimer’s disease: new biomarkers and treatment targets? Neuromolecular Med 12(4):331–340. https://doi.org/10.1007/s12017-010-8121-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mielke MM, Bandaru VV, Haughey NJ, Xia 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(7):633–641. https://doi.org/10.1212/WNL.0b013e318264e380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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(7):2070–2075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Haughey NJ, Bandaru VV, Bae M (1801) Mattson MP (2010) Roles for dysfunctional sphingolipid metabolism in Alzheimer’s disease neuropathogenesis. Biochim Biophys Acta 8:878–886. https://doi.org/10.1016/j.bbalip.2010.05.003

    Article  CAS  Google Scholar 

  31. Krishnamurthy K, Dasgupta S, Bieberich E (2007) Development and characterization of a novel anti-ceramide antibody. J Lipid Res 48(4):968–975

    Article  CAS  PubMed  Google Scholar 

  32. Demetrius LA, Simon DK (2012) An inverse-Warburg effect and the origin of Alzheimer’s disease. Biogerontology 13(6):583–594. https://doi.org/10.1007/s10522-012-9403-6

    Article  CAS  PubMed  Google Scholar 

  33. Tavallaie M, Voshtani R, Deng X, Qiao Y, Jiang F, Collman JP, Fu L (2020) Moderation of mitochondrial respiration mitigates metabolic syndrome of aging. Proc Natl Acad Sci U S A 117(18):9840–9850. https://doi.org/10.1073/pnas.1917948117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zheng J, Xie Y, Ren L, Qi L, Wu L, Pan X, Zhou J, Chen Z, Liu L (2021) GLP-1 improves the supportive ability of astrocytes to neurons by promoting aerobic glycolysis in Alzheimer’s disease. Mol Metab:101180. https://doi.org/10.1016/j.molmet.2021.101180

  35. Yoshimura S, Banno Y, Nakashima S, Hayashi K, Yamakawa H, Sawada M, Sakai N, Nozawa Y (1999) Inhibition of neutral sphingomyelinase activation and ceramide formation by glutathione in hypoxic PC12 cell death. J Neurochem 73(2):675–683. https://doi.org/10.1046/j.1471-4159.1999.0730675.x

    Article  CAS  PubMed  Google Scholar 

  36. Denisova NA, Cantuti-Castelvetri I, Hassan WN, Paulson KE, Joseph JA (2001) Role of membrane lipids in regulation of vulnerability to oxidative stress in PC12 cells: implication for aging. Free Radic Biol Med 30(6):671–678. https://doi.org/10.1016/s0891-5849(00)00513-x

    Article  CAS  PubMed  Google Scholar 

  37. Sofic E, Denisova N, Youdim K, Vatrenjak-Velagic V, De Filippo C, Mehmedagic A, Causevic A, Cao G, Joseph JA, Prior RL (2001) Antioxidant and pro-oxidant capacity of catecholamines and related compounds. Effects of hydrogen peroxide on glutathione and sphingomyelinase activity in pheochromocytoma PC12 cells: potential relevance to age-related diseases. J Neural Transm (Vienna) 108(5):541–557. https://doi.org/10.1007/s007020170055

    Article  CAS  Google Scholar 

  38. Ichi I, Kamikawa C, Nakagawa T, Kobayashi K, Kataoka R, Nagata E, Kitamura Y, Nakazaki C, Matsura T, Kojo S (2009) Neutral sphingomyelinase-induced ceramide accumulation by oxidative stress during carbon tetrachloride intoxication. Toxicology 261(1–2):33–40. https://doi.org/10.1016/j.tox.2009.04.040

    Article  CAS  PubMed  Google Scholar 

  39. Skvarc DR, Dean OM, Byrne LK, Gray L, Lane S, Lewis M, Fernandes BS, Berk M, Marriott A (2017) The effect of N-acetylcysteine (NAC) on human cognition - a systematic review. Neurosci Biobehav Rev 78:44–56. https://doi.org/10.1016/j.neubiorev.2017.04.013

    Article  CAS  PubMed  Google Scholar 

  40. Cao L, Li L, Zuo Z (2012) N-acetylcysteine reverses existing cognitive impairment and increased oxidative stress in glutamate transporter type 3 deficient mice. Neuroscience 220:85–89. https://doi.org/10.1016/j.neuroscience.2012.06.044

    Article  CAS  PubMed  Google Scholar 

  41. Farr SA, Poon HF, Dogrukol-Ak D, Drake J, Banks WA, Eyerman E, Butterfield DA, Morley JE (2003) The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice. J Neurochem 84(5):1173–1183

    Article  CAS  PubMed  Google Scholar 

  42. Cohen J, Torres C (2019) Astrocyte senescence: evidence and significance. Aging Cell 18(3):e12937. https://doi.org/10.1111/acel.12937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Escartin C, Galea E, Lakatos A, O’Callaghan JP, Petzold GC, Serrano-Pozo A, Steinhauser C, Volterra A, Carmignoto G, Agarwal A, Allen NJ, Araque A, Barbeito L, Barzilai A, Bergles DE, Bonvento G, Butt AM, Chen WT, Cohen-Salmon M, Cunningham C, Deneen B, De Strooper B, Diaz-Castro B, Farina C, Freeman M, Gallo V, Goldman JE, Goldman SA, Gotz M, Gutierrez A, Haydon PG, Heiland DH, Hol EM, Holt MG, Iino M, Kastanenka KV, Kettenmann H, Khakh BS, Koizumi S, Lee CJ, Liddelow SA, MacVicar BA, Magistretti P, Messing A, Mishra A, Molofsky AV, Murai KK, Norris CM, Okada S, Oliet SHR, Oliveira JF, Panatier A, Parpura V, Pekna M, Pekny M, Pellerin L, Perea G, Perez-Nievas BG, Pfrieger FW, Poskanzer KE, Quintana FJ, Ransohoff RM, Riquelme-Perez M, Robel S, Rose CR, Rothstein JD, Rouach N, Rowitch DH, Semyanov A, Sirko S, Sontheimer H, Swanson RA, Vitorica J, Wanner IB, Wood LB, Wu J, Zheng B, Zimmer ER, Zorec R, Sofroniew MV, Verkhratsky A (2021) Reactive astrocyte nomenclature, definitions, and future directions. Nat Neurosci 24(3):312–325. https://doi.org/10.1038/s41593-020-00783-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. O’Callaghan JP, Kelly KA, VanGilder RL, Sofroniew MV, Miller DB (2014) Early activation of STAT3 regulates reactive astrogliosis induced by diverse forms of neurotoxicity. PLoS ONE 9(7):e102003. https://doi.org/10.1371/journal.pone.0102003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hashioka S, Klegeris A, Qing H, McGeer PL (2011) STAT3 inhibitors attenuate interferon-gamma-induced neurotoxicity and inflammatory molecule production by human astrocytes. Neurobiol Dis 41(2):299–307. https://doi.org/10.1016/j.nbd.2010.09.018

    Article  CAS  PubMed  Google Scholar 

  46. Herrmann JE, Imura T, Song B, Qi J, Ao Y, Nguyen TK, Korsak RA, Takeda K, Akira S, Sofroniew MV (2008) STAT3 is a critical regulator of astrogliosis and scar formation after spinal cord injury. J Neurosci 28(28):7231–7243. https://doi.org/10.1523/JNEUROSCI.1709-08.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. White CW 3rd, Fan X, Maynard JC, Wheatley EG, Bieri G, Couthouis J, Burlingame AL, Villeda SA (2020) Age-related loss of neural stem cell O-GlcNAc promotes a glial fate switch through STAT3 activation. Proc Natl Acad Sci U S A 117(36):22214–22224. https://doi.org/10.1073/pnas.2007439117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhang Y, Ji F, Wang G, He D, Yang L, Zhang M (2018) BDNF activates mTOR to upregulate NR2B expression in the rostral anterior cingulate cortex required for inflammatory pain-related aversion in rats. Neurochem Res 43(3):681–691. https://doi.org/10.1007/s11064-018-2470-6

    Article  CAS  PubMed  Google Scholar 

  49. Gozlan H, Khazipov R, Ben-Ari Y (1995) Multiple forms of long-term potentiation and multiple regulatory sites of N-methyl-D-aspartate receptors: role of the redox site. J Neurobiol 26(3):360–369. https://doi.org/10.1002/neu.480260308

    Article  CAS  PubMed  Google Scholar 

  50. Rodenas-Ruano A, Chavez AE, Cossio MJ, Castillo PE, Zukin RS (2012) REST-dependent epigenetic remodeling promotes the developmental switch in synaptic NMDA receptors. Nat Neurosci 15(10):1382–1390. https://doi.org/10.1038/nn.3214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Harraz MM, Eacker SM, Wang X, Dawson TM, Dawson VL (2012) MicroRNA-223 is neuroprotective by targeting glutamate receptors. Proc Natl Acad Sci U S A 109(46):18962–18967. https://doi.org/10.1073/pnas.1121288109

    Article  PubMed  PubMed Central  Google Scholar 

  52. Amoah SK, Rodriguez BA, Logothetis CN, Chander P, Sellgren CM, Weick JP, Sheridan SD, Jantzie LL, Webster MJ, Mellios N (2020) Exosomal secretion of a psychosis-altered miRNA that regulates glutamate receptor expression is affected by antipsychotics. Neuropsychopharmacology 45(4):656–665. https://doi.org/10.1038/s41386-019-0579-1

    Article  CAS  PubMed  Google Scholar 

  53. Zhu Y, Carvey PM, Ling Z (2006) Age-related changes in glutathione and glutathione-related enzymes in rat brain. Brain Res 1090(1):35–44. https://doi.org/10.1016/j.brainres.2006.03.063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Bhatia TN, Pant DB, Eckhoff EA, Gongaware RN, Do T, Hutchison DF, Gleixner AM, Leak RK (2019) astrocytes do not forfeit their neuroprotective roles after surviving intense oxidative stress. Front Mol Neurosci 12:87. https://doi.org/10.3389/fnmol.2019.00087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Liu B, Andrieu-Abadie N, Levade T, Zhang P, Obeid LM, Hannun YA (1998) Glutathione regulation of neutral sphingomyelinase in tumor necrosis factor-alpha-induced cell death. J Biol Chem 273(18):11313–11320

    Article  CAS  PubMed  Google Scholar 

  56. Tang YP, Shimizu E, Dube GR, Rampon C, Kerchner GA, Zhuo M, Liu G, Tsien JZ (1999) Genetic enhancement of learning and memory in mice. Nature 401(6748):63–69. https://doi.org/10.1038/43432

    Article  CAS  PubMed  Google Scholar 

  57. Cao X, Cui Z, Feng R, Tang YP, Qin Z, Mei B, Tsien JZ (2007) Maintenance of superior learning and memory function in NR2B transgenic mice during ageing. Eur J Neurosci 25(6):1815–1822. https://doi.org/10.1111/j.1460-9568.2007.05431.x

    Article  PubMed  Google Scholar 

  58. Avila J, Llorens-Martin M, Pallas-Bazarra N, Bolos M, Perea JR, Rodriguez-Matellan A, Hernandez F (2017) Cognitive decline in neuronal aging and Alzheimer’s disease: role of NMDA receptors and associated proteins. Front Neurosci 11:626. https://doi.org/10.3389/fnins.2017.00626

    Article  PubMed  PubMed Central  Google Scholar 

  59. Kalinichenko LS, Abdel-Hafiz L, Wang AL, Muhle C, Rosel N, Schumacher F, Kleuser B, Smaga I, Frankowska M, Filip M, Schaller G, Richter-Schmidinger T, Lenz B, Gulbins E, Kornhuber J, Oliveira AWC, Barros M, Huston JP, Muller CP (2021) Neutral sphingomyelinase is an affective valence-dependent regulator of learning and memory. Cereb Cortex 31(2):1316–1333. https://doi.org/10.1093/cercor/bhaa298

    Article  PubMed  Google Scholar 

  60. Tabatadze N, Savonenko A, Song H, Bandaru VV, Chu M, Haughey NJ (2010) Inhibition of neutral sphingomyelinase-2 perturbs brain sphingolipid balance and spatial memory in mice. J Neurosci Res 88(13):2940–2951. https://doi.org/10.1002/jnr.22438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Sacket SJ, Chung HY, Okajima F, Im DS (2009) Increase in sphingolipid catabolic enzyme activity during aging. Acta Pharmacol Sin 30(10):1454–1461. https://doi.org/10.1038/aps.2009.136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Zhong L, Jiang X, Zhu Z, Qin H, Dinkins MB, Kong JN, Leanhart S, Wang R, Elsherbini A, Bieberich E, Zhao Y, Wang G (2019) Lipid transporter Spns2 promotes microglia pro-inflammatory activation in response to amyloid-beta peptide. Glia 67(3):498–511. https://doi.org/10.1002/glia.23558

    Article  PubMed  Google Scholar 

  63. Lu FB, Chen DZ, Chen L, Hu ED, Wu JL, Li H, Gong YW, Lin Z, Wang XD, Li J, Jin XY, Xu LM, Chen YP (2019) Attenuation of experimental autoimmune hepatitis in mice with bone mesenchymal stem cell-derived exosomes carrying MicroRNA-223-3p. Mol Cells 42(12):906–918. https://doi.org/10.14348/molcells.2019.2283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the Department of Physiology (Chair Dr. Alan Daugherty) at the University of Kentucky, Lexington, KY, for institutional support.

Funding

This work was supported in part by NIH grants R01NS095215, R01AG034389, and R01AG064234, and the VA grant I01BX003643 to EB. This work was also supported in part by a BrightFocus grant (A20201464F) to SMC. The lipidomics analysis of this study was supported in part by the Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina (P30 CA138313 and P30 GM103339).

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Authors and Affiliations

  1. Department of Physiology, College of Medicine, University of Kentucky, 780 Rose St., Room MS519, Lexington, KY, 40536, USA

    Zhihui Zhu, Zainuddin Quadri, Simone M. Crivelli, Ahmed Elsherbini, Liping Zhang, Priyanka Tripathi, Haiyan Qin, Emily Roush, Stefka D. Spassieva, Mariana Nikolova-Karakashian, Timothy S. McClintock & Erhard Bieberich

  2. Veterans Affairs Medical Center, Lexington, KY, 40502, USA

    Zainuddin Quadri, Liping Zhang, Priyanka Tripathi & Erhard Bieberich

  3. Department of Physiology, College of Medicine, University of Kentucky, 780 Rose St., Room MS517A, Lexington, KY, 40536, USA

    Stefka D. Spassieva

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Contributions

ZZ, ZQ, SMC, AE, LZ, PT, HQ, and ER planned and performed experiments, analyzed data, and wrote the manuscript; SDS, MNK, and TSM planned experiments, analyzed data, and wrote the manuscript. E.B. supervised study, planned and performed experiments, analyzed data, and wrote the manuscript.

Corresponding author

Correspondence to Erhard Bieberich.

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Ethics Approval

Mice were handled according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals. All procedures involving mice were approved by the Institutional Animal Care and Use Committee of University of Kentucky. This study did not involve human subjects.

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Not applicable (no data from individual human subjects).

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Not applicable (no data from individual human subjects).

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The authors declare no competing interests.

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Zhu, Z., Quadri, Z., Crivelli, S.M. et al. Neutral Sphingomyelinase 2 Mediates Oxidative Stress Effects on Astrocyte Senescence and Synaptic Plasticity Transcripts. Mol Neurobiol 59, 3233–3253 (2022). https://doi.org/10.1007/s12035-022-02747-0

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  • DOI: https://doi.org/10.1007/s12035-022-02747-0

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