Inhibition of acid sphingomyelinase reduces reactive astrocyte secretion of mitotoxic extracellular vesicles and improves Alzheimer's disease pathology in the 5xFAD mouse.
5xFAD
Acid sphingomyelinase
Astrocytes
C1q
Extracellular vesicle
IL-1α
Imipramine
Microglia
Mitochondria
TNF-α
Journal
Acta neuropathologica communications
ISSN: 2051-5960
Titre abrégé: Acta Neuropathol Commun
Pays: England
ID NLM: 101610673
Informations de publication
Date de publication:
21 08 2023
21 08 2023
Historique:
received:
15
06
2023
accepted:
05
08
2023
medline:
23
8
2023
pubmed:
22
8
2023
entrez:
22
8
2023
Statut:
epublish
Résumé
In Alzheimer's disease (AD), reactive astrocytes produce extracellular vesicles (EVs) that affect mitochondria in neurons. Here, we show that Aβ-induced generation of the sphingolipid ceramide by acid sphingomyelinase (A-SMase) triggered proinflammatory cytokine (C1q, TNF-α, IL-1α) release by microglia, which induced the reactive astrocytes phenotype and secretion of EVs enriched with ceramide. These EVs impeded the capacity of neurons to respond to energy demand. Inhibition of A-SMase with Arc39 and Imipramine reduced the secretion of cytokines from microglia, prompting us to test the effect of Imipramine on EV secretion and AD pathology in the 5xFAD mouse model. Brain derived-EVs from 5xFAD mice treated with Imipramine contained reduced levels of the astrocytic marker GFAP, ceramide, and Aβ and did not impair mitochondrial respiration when compared to EVs derived from untreated 5xFAD brain. Consistently, Imipramine-treated 5xFAD mice showed reduced AD pathology. Our study identifies A-SMase inhibitors as potential AD therapy by preventing cyotokine-elicited secretion of mitotoxic EVs from astrocytes.
Identifiants
pubmed: 37605262
doi: 10.1186/s40478-023-01633-7
pii: 10.1186/s40478-023-01633-7
pmc: PMC10440899
doi:
Substances chimiques
Sphingomyelin Phosphodiesterase
EC 3.1.4.12
Imipramine
OGG85SX4E4
Ceramides
0
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
135Subventions
Organisme : NIA NIH HHS
ID : R21 AG078601
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG064234
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG028383
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG034389
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG078338
Pays : United States
Organisme : BLRD VA
ID : I01 BX003643
Pays : United States
Informations de copyright
© 2023. BioMed Central Ltd., part of Springer Nature.
Références
Couttas TA et al (2018) Age-dependent changes to sphingolipid balance in the human hippocampus are gender-specific and may sensitize to neurodegeneration. J Alzheimers Dis 63:503–514. https://doi.org/10.3233/JAD-171054
doi: 10.3233/JAD-171054
pubmed: 29660940
Cutler RG et al (2004) Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer’s disease. Proceed Nat Acad Sci USA 101:2070–2075. https://doi.org/10.1073/pnas.0305799101
doi: 10.1073/pnas.0305799101
Han X, McKeel DMH, Kelley DW, Kelley J, Morris JC (2002) Substantial sulfatide deficiency and ceramide elevation in very early Alzheimer’s disease: potential role in disease pathogenesis. J Neurochem 82(809):818
Filippov V et al (2012) Increased ceramide in brains with Alzheimer’s and other neurodegenerative diseases. J Alzheimers Dis 29:537–547. https://doi.org/10.3233/JAD-2011-111202
doi: 10.3233/JAD-2011-111202
pubmed: 22258513
pmcid: 3643694
Mielke MM et al (2010) Serum sphingomyelins and ceramides are early predictors of memory impairment. Neurobiol Aging 31:17–24. https://doi.org/10.1016/j.neurobiolaging.2008.03.011
doi: 10.1016/j.neurobiolaging.2008.03.011
pubmed: 18455839
Mielke MM et al (2012) Serum ceramides increase the risk of Alzheimer disease: the Women’s Health and Aging Study II. Neurology 79:633–641. https://doi.org/10.1212/WNL.0b013e318264e380
doi: 10.1212/WNL.0b013e318264e380
pubmed: 22815558
pmcid: 3414665
Fonteh AN et al (2015) Sphingolipid metabolism correlates with cerebrospinal fluid Beta amyloid levels in Alzheimer’s disease. PLoS One 10:e0125597. https://doi.org/10.1371/journal.pone.0125597
doi: 10.1371/journal.pone.0125597
pubmed: 25938590
pmcid: 4418746
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. https://doi.org/10.1007/s11064-007-9297-x
doi: 10.1007/s11064-007-9297-x
pubmed: 17342407
He X, Huang Y, Li B, Gong CX, Schuchman EH (2010) Deregulation of sphingolipid metabolism in Alzheimer’s disease. Neurobiol Aging 31:398–408. https://doi.org/10.1016/j.neurobiolaging.2008.05.010
doi: 10.1016/j.neurobiolaging.2008.05.010
pubmed: 18547682
Crivelli SM et al (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
doi: 10.1016/j.addr.2019.12.003
pubmed: 31911096
Lee JK et al (2014) Acid sphingomyelinase modulates the autophagic process by controlling lysosomal biogenesis in Alzheimer’s disease. J Exp Med 211:1551–1570. https://doi.org/10.1084/jem.20132451
doi: 10.1084/jem.20132451
pubmed: 25049335
pmcid: 4113944
Li X, Gulbins E, Zhang Y (2012) Oxidative stress triggers Ca-dependent lysosome trafficking and activation of acid sphingomyelinase. Cell Physiol Biochem 30:815–826. https://doi.org/10.1159/000341460
doi: 10.1159/000341460
pubmed: 22890197
Wiegmann K, Schutze S, Machleidt T, Witte D, Kronke M (1994) Functional dichotomy of neutral and acidic sphingomyelinases in tumor necrosis factor signaling. Cell 78:1005–1015. https://doi.org/10.1016/0092-8674(94)90275-5
doi: 10.1016/0092-8674(94)90275-5
pubmed: 7923351
Butterfield DA, Lauderback CM (2002) Lipid peroxidation and protein oxidation in Alzheimer’s disease brain: potential causes and consequences involving amyloid beta-peptide-associated free radical oxidative stress. Free Radic Biol Med 32:1050–1060. https://doi.org/10.1016/s0891-5849(02)00794-3
doi: 10.1016/s0891-5849(02)00794-3
pubmed: 12031889
Liddelow SA et al (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481–487. https://doi.org/10.1038/nature21029
doi: 10.1038/nature21029
pubmed: 28099414
pmcid: 5404890
Wang G et al (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 287:21384–21395. https://doi.org/10.1074/jbc.M112.340513
doi: 10.1074/jbc.M112.340513
pubmed: 22532571
pmcid: 3375560
Dinkins MB, Dasgupta S, Wang G, Zhu G (2014) & 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. https://doi.org/10.1016/j.neurobiolaging.2014.02.012
doi: 10.1016/j.neurobiolaging.2014.02.012
pubmed: 24650793
pmcid: 4035236
Kim MH et al (2017) Hepatic inflammatory cytokine production can be regulated by modulating sphingomyelinase and ceramide synthase 6. Int J Mol Med 39:453–462. https://doi.org/10.3892/ijmm.2016.2835
doi: 10.3892/ijmm.2016.2835
pubmed: 28035360
Albouz S et al (1981) Tricyclic antidepressants induce sphingomyelinase deficiency in fibroblast and neuroblastoma cell cultures. Biomedicine 35:218–220
pubmed: 6285997
Yoshida Y et al (1985) Reduction of acid sphingomyelinase activity in human fibroblasts induced by AY-9944 and other cationic amphiphilic drugs. J Biochem 98:1669–1679
doi: 10.1093/oxfordjournals.jbchem.a135438
pubmed: 2419314
Kolzer M, Werth N, Sandhoff K (2004) Interactions of acid sphingomyelinase and lipid bilayers in the presence of the tricyclic antidepressant desipramine. FEBS Lett 559:96–98. https://doi.org/10.1016/S0014-5793(04)00033-X
doi: 10.1016/S0014-5793(04)00033-X
pubmed: 14960314
Hurwitz R, Ferlinz K, Sandhoff K (1994) The tricyclic antidepressant desipramine causes proteolytic degradation of lysosomal sphingomyelinase in human fibroblasts. Biol Chem Hoppe Seyler 375:447–450
doi: 10.1515/bchm3.1994.375.7.447
pubmed: 7945993
Kornhuber J et al (2010) 2010 Functional Inhibitors of Acid Sphingomyelinase (FIASMAs): a novel pharmacological group of drugs with broad clinical applications. Cell Physiol Biochem 26:9–20. https://doi.org/10.1159/000315101
doi: 10.1159/000315101
pubmed: 20502000
Crivelli SM et al (2022) Function of ceramide transfer protein for biogenesis and sphingolipid composition of extracellular vesicles. J Extracell Vesicles 11:e12233. https://doi.org/10.1002/jev2.12233
doi: 10.1002/jev2.12233
pubmed: 35642450
pmcid: 9156972
Crivelli SM et al (2020) Ceramide analog [18F]F-HPA-12 detects sphingolipid disbalance in the brain of Alzheimer’s disease transgenic mice by functioning as a metabolic probe. Scient Reports 10:19354. https://doi.org/10.1038/s41598-020-76335-4
doi: 10.1038/s41598-020-76335-4
Crivelli SM et al (2021) CERTL reduces C16 ceramide, amyloid-beta levels, and inflammation in a model of Alzheimer’s disease. Alzheimers Res Ther 13:45. https://doi.org/10.1186/s13195-021-00780-0
doi: 10.1186/s13195-021-00780-0
pubmed: 33597019
pmcid: 7890977
Elsherbini A et al (2023) Novel isolation method reveals sex-specific composition and neurotoxicity of small extracellular vesicles in a mouse model of alzheimer’s disease. Cells 12(12):1623. https://doi.org/10.3390/cells12121623
doi: 10.3390/cells12121623
pubmed: 37371093
pmcid: 10297289
Hubbard WB, Harwood CL, Geisler JG, Vekaria HJ, Sullivan PG (2018) Mitochondrial uncoupling prodrug improves tissue sparing, cognitive outcome, and mitochondrial bioenergetics after traumatic brain injury in male mice. J Neurosci Res 96:1677–1688. https://doi.org/10.1002/jnr.24271
doi: 10.1002/jnr.24271
pubmed: 30063076
pmcid: 6129401
Bielawski J et al (2010) Sphingolipid analysis by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Adv Exp Med Biol 688:46–59. https://doi.org/10.1007/978-1-4419-6741-1_3
doi: 10.1007/978-1-4419-6741-1_3
pubmed: 20919645
Bielawski J et al (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
doi: 10.1007/978-1-60761-322-0_22
pubmed: 19763489
Sakata A et al (2007) Acid sphingomyelinase inhibition suppresses lipopolysaccharide-mediated release of inflammatory cytokines from macrophages and protects against disease pathology in dextran sulphate sodium-induced colitis in mice. Immunology 122:54–64. https://doi.org/10.1111/j.1365-2567.2007.02612.x
doi: 10.1111/j.1365-2567.2007.02612.x
pubmed: 17451462
pmcid: 2265987
Bai A, Guo Y (2017) Acid sphingomyelinase mediates human CD4(+) T-cell signaling: potential roles in T-cell responses and diseases. Cell Death Dis 8:e2963. https://doi.org/10.1038/cddis.2017.3603
doi: 10.1038/cddis.2017.3603
pubmed: 28749465
pmcid: 5550889
Zhu Z et al (2022) Neutral sphingomyelinase 2 mediates oxidative stress effects on astrocyte senescence and synaptic plasticity transcripts. Mol Neurobiol 59:3233–3253. https://doi.org/10.1007/s12035-022-02747-0
doi: 10.1007/s12035-022-02747-0
pubmed: 35294731
pmcid: 9023069
de Wit NM et al (2019) Astrocytic ceramide as possible indicator of neuroinflammation. J Neuroinflammation 16:48. https://doi.org/10.1186/s12974-019-1436-1
doi: 10.1186/s12974-019-1436-1
pubmed: 30803453
pmcid: 6388480
Elsherbini A et al (2020) Association of Abeta with ceramide-enriched astrosomes mediates Abeta neurotoxicity. Acta Neuropathol Commun 8:60. https://doi.org/10.1186/s40478-020-00931-8
doi: 10.1186/s40478-020-00931-8
pubmed: 32345374
pmcid: 7189561
Chaudhuri AD et al (2018) TNFalpha and IL-1beta modify the miRNA cargo of astrocyte shed extracellular vesicles to regulate neurotrophic signaling in neurons. Cell Death Dis 9:363. https://doi.org/10.1038/s41419-018-0369-4
doi: 10.1038/s41419-018-0369-4
pubmed: 29507357
pmcid: 5838212
Wang K et al (2017) TNF-alpha promotes extracellular vesicle release in mouse astrocytes through glutaminase. J Neuroinflammation 14:87. https://doi.org/10.1186/s12974-017-0853-2
doi: 10.1186/s12974-017-0853-2
pubmed: 28427419
pmcid: 5399318
Willis CM, Sutter P, Rouillard M, Crocker SJ (2020) The effects of IL-1beta on astrocytes are conveyed by extracellular vesicles and influenced by Age. Neurochem Res 45:694–707. https://doi.org/10.1007/s11064-019-02937-8
doi: 10.1007/s11064-019-02937-8
pubmed: 31900795
Elsherbini A, Bieberich E (2018) Ceramide and exosomes: a novel target in cancer biology and therapy. Adv Cancer Res 140:121–154. https://doi.org/10.1016/bs.acr.2018.05.004
doi: 10.1016/bs.acr.2018.05.004
pubmed: 30060807
pmcid: 6109973
Girard SD et al (2014) Onset of hippocampus-dependent memory impairments in 5XFAD transgenic mouse model of Alzheimer’s disease. Hippocampus 24:762–772. https://doi.org/10.1002/hipo.22267
doi: 10.1002/hipo.22267
pubmed: 24596271
Savage JC et al (2015) Nuclear receptors license phagocytosis by trem2+ myeloid cells in mouse models of Alzheimer’s disease. J Neurosci 35:6532–6543. https://doi.org/10.1523/JNEUROSCI.4586-14.2015
doi: 10.1523/JNEUROSCI.4586-14.2015
pubmed: 25904803
pmcid: 4405560
Asiimwe N, Yeo SG, Kim MS, Jung J, Jeong NY (2015) Nitric oxide: exploring the contextual link with Alzheimer’s disease. Oxid Med Cell Longev 2016:7205747. https://doi.org/10.1155/2016/7205747
doi: 10.1155/2016/7205747
Mokhber N et al (2014) Comparison of sertraline, venlafaxine and desipramine effects on depression, cognition and the daily living activities in Alzheimer patients. Pharmacopsychiatry 47:131–140. https://doi.org/10.1055/s-0034-1377041
doi: 10.1055/s-0034-1377041
pubmed: 24955552
Heppner FL, Ransohoff RM, Becher B (2015) Immune attack: the role of inflammation in Alzheimer disease. Nature reviews. Neuroscience 16:358–372. https://doi.org/10.1038/nrn38803
doi: 10.1038/nrn38803
pubmed: 25991443
Efthymiou AG, Goate AM (2017) Late onset Alzheimer’s disease genetics implicates microglial pathways in disease risk. Mol Neurodegener 12:43. https://doi.org/10.1186/s13024-017-0184-x
doi: 10.1186/s13024-017-0184-x
pubmed: 28549481
pmcid: 5446752
Cuschieri J, Bulger E, Billgrin J, Garcia I, Maier RV (2007) Acid sphingomyelinase is required for lipid Raft TLR4 complex formation. Surg Infect (Larchmt) 8:91–106. https://doi.org/10.1089/sur.2006.050
doi: 10.1089/sur.2006.050
pubmed: 17381401
Dinkins MB et al (2016) Neutral sphingomyelinase-2 deficiency ameliorates alzheimer’s disease pathology and improves cognition in the 5XFAD mouse. J Neurosci 36:8653–8667. https://doi.org/10.1523/JNEUROSCI.1429-16.2016
doi: 10.1523/JNEUROSCI.1429-16.2016
pubmed: 27535912
pmcid: 4987436
Sala M et al (2020) Novel Human Neutral Sphingomyelinase 2 Inhibitors as Potential Therapeutics for Alzheimer’s Disease. J Med Chem 63:6028–6056. https://doi.org/10.1021/acs.jmedchem.0c00278
doi: 10.1021/acs.jmedchem.0c00278
pubmed: 32298582
pmcid: 8025741
Bianco F et al (2009) Acid sphingomyelinase activity triggers microparticle release from glial cells. EMBO J 28:1043–1054. https://doi.org/10.1038/emboj.2009.45
doi: 10.1038/emboj.2009.45
pubmed: 19300439
pmcid: 2664656
Zbinden-Foncea H, Deldicque L, Pierre N, Francaux M, Raymackers JM (2012) TLR2 and TLR4 activation induces p38 MAPK-dependent phosphorylation of S6 kinase 1 in C2C12 myotubes. Cell Biol Int 36:1107–1113. https://doi.org/10.1042/CBI20120081
doi: 10.1042/CBI20120081
pubmed: 22931089
Mathieu M et al (2021) Specificities of exosome versus small ectosome secretion revealed by live intracellular tracking of CD63 and CD9. Nat Commun 12:4389. https://doi.org/10.1038/s41467-021-24384-2
doi: 10.1038/s41467-021-24384-2
pubmed: 34282141
pmcid: 8289845
Zhu Z et al (2023) The S1P receptor 1 antagonist Ponesimod reduces TLR4-induced neuroinflammation and increases Abeta clearance in 5XFAD mice. EBioMedicine 94:104713. https://doi.org/10.1016/j.ebiom.2023.104713
doi: 10.1016/j.ebiom.2023.104713
pubmed: 37480622
pmcid: 10393615
Berger AK, Fratiglioni L, Winblad B, Backman L (2005) Alzheimer’s disease and depression: preclinical comorbidity effects on cognitive functioning. Cortex 41:603–612
doi: 10.1016/S0010-9452(08)70200-4
pubmed: 16042036
Wang DD et al (2016) Desipramine improves depression-like behavior and working memory by up-regulating p-CREB in Alzheimer’s disease associated mice. J Integr Neurosci 15:247–260. https://doi.org/10.1142/S021963521650014X
doi: 10.1142/S021963521650014X
pubmed: 27338163
Cirrito JR et al (2011) Serotonin signaling is associated with lower amyloid-beta levels and plaques in transgenic mice and humans. Proceed Nat Acad Sci USA 108:14968–14973. https://doi.org/10.1073/pnas.1107411108
doi: 10.1073/pnas.1107411108
Nelson RL et al (2007) Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice. Exp Neurol 205:166–176. https://doi.org/10.1016/j.expneurol.2007.01.037
doi: 10.1016/j.expneurol.2007.01.037
pubmed: 17368447
pmcid: 1979096
Kornhuber J et al (2011) Identification of novel functional inhibitors of acid sphingomyelinase. PLoS One 6:e23852. https://doi.org/10.1371/journal.pone.0023852
doi: 10.1371/journal.pone.0023852
pubmed: 21909365
pmcid: 3166082
Gulbins E et al (2015) A central role for the acid sphingomyelinase/ceramide system in neurogenesis and major depression. J Neurochem 134:183–192. https://doi.org/10.1111/jnc.13145
doi: 10.1111/jnc.13145
pubmed: 25925550
Kornhuber J, Muller CP, Becker KA, Reichel M, Gulbins E (2014) The ceramide system as a novel antidepressant target. Trends Pharmacol Sci 35:293–304. https://doi.org/10.1016/j.tips.2014.04.003
doi: 10.1016/j.tips.2014.04.003
pubmed: 24793541
Choi BJ et al (2023) Immunotherapy targeting plasma ASM is protective in a mouse model of Alzheimer’s disease. Nat Commun 14:1631. https://doi.org/10.1038/s41467-023-37316-z
doi: 10.1038/s41467-023-37316-z
pubmed: 36959217
pmcid: 10036484
Park MH et al (2022) Discovery of a dual-action small molecule that improves neuropathological features of Alzheimer’s disease mice. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.2115082119
doi: 10.1073/pnas.2115082119
pubmed: 36577057
pmcid: 9910428
von Linstow CU et al (2017) Serotonin augmentation therapy by escitalopram has minimal effects on amyloid-beta levels in early-stage Alzheimer’s-like disease in mice. Alzheimers Res Ther 9:74. https://doi.org/10.1186/s13195-017-0298-y
doi: 10.1186/s13195-017-0298-y
Arenz C (2010) Small molecule inhibitors of acid sphingomyelinase. Cell Physiol Biochem 26:1–8. https://doi.org/10.1159/000315100
doi: 10.1159/000315100
pubmed: 20501999