ArticleJournal of molecular medicine (Berlin, Germany)2022
Stress induces major depressive disorder by a neutral sphingomyelinase 2-mediated accumulation of ceramide-enriched exosomes in the blood plasma.
Article in Journal of molecular medicine (Berlin, Germany), 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 29 citations in OpenAlex.
- The role of sphingolipids in major depressive disorder and associated cognitive impairment: interactions with monoaminergic signaling, neuroinflammation, and neurogenesis.Molecular psychiatry · 2026Review
- Untargeted plasma metabolomics identifies metabolite signatures associated with suicidality status in chronic schizophrenia.European archives of psychiatry and clinical neuroscience · 2026Article
- Sphingolipids in Emotional Well-Being.Journal of neurochemistry · 2026Review
- Ceramides and neuroinflammation as immunometabolic drivers and biomarkers of major depressive disorder, treatment-resistant depression, and suicidal vulnerability.Frontiers in pharmacology · 2026Review
- Psychosomatic - psychotherapeutic treatment of stress-related disorders impacts the sphingolipid metabolism towards increased sphingosine and sphingosine-1-phosphate levels.European archives of psychiatry and clinical neuroscience · 2025Article
- Acid sphingomyelinase activity suggests a new antipsychotic pharmaco-treatment strategy for schizophrenia.Molecular psychiatry · 2025Article
- Exercise improves depressive-like behavior in adolescent mice by regulating sphingosine and ceramide metabolism through microglial CerS1.Communications biology · 2025Article
- Update on the roles and applications of extracellular vesicles in depression.World journal of psychiatry · 2025Review
- Phosphatidic acid is involved in regulation of autophagy in neurons in vitro and in vivo.Pflugers Archiv : European journal of physiology · 2024Article
- Biofluid-Derived Exosomal LncRNAs: Their Potential in Obesity and Related Comorbidities.Biology · 2024Review
- The multiple roles of chronic stress and glucocorticoids in Alzheimer's disease pathogenesis.Trends in neurosciences · 2024Review
- Gut microbiota dysbiosis-mediated ceramides elevation contributes to corticosterone-induced depression by impairing mitochondrial function.NPJ biofilms and microbiomes · 2024Article
- Protein Tyrosine Phosphatase 1B (PTP1B): A Comprehensive Review of Its Role in Pathogenesis of Human Diseases.International journal of molecular sciences · 2024Review
- The Role of Neutral Sphingomyelinase-2 (NSM2) in the Control of Neutral Lipid Storage in T Cells.International journal of molecular sciences · 2024Article
- Stress, microRNAs, and stress-related psychiatric disorders: an overview.Molecular psychiatry · 2023Review
- Role of Tyrosine Nitrosylation in Stress-Induced Major Depressive Disorder: Mechanisms and Implications.International journal of molecular sciences · 2023Article
- Research progress in role of exosomes exosomes in mental disorders.Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2023Article
- Characterization of a Neutral Sphingomyelinase Activity in Human Serum and Plasma.International journal of molecular sciences · 2023Article
- Lipids in major depressive disorder: new kids on the block or old friends revisited?Frontiers in psychiatry · 2023Review
- Depression Pathophysiology: Astrocyte Mitochondrial Melatonergic Pathway as Crucial Hub.International journal of molecular sciences · 2022Review
Corrections and comments
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Authors and funding
12 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Major depressive disorder (MDD) is a very common, severe disease with a lifetime prevalence of ~ 10%. The pathogenesis of MDD is unknown and, unfortunately, therapy is often insufficient. We have previously reported that ceramide levels are increased in the blood plasma of patients with MDD and in mice with experimental MDD. Here, we demonstrate that ceramide-enriched exosomes in the blood plasma are increased in mice with stress-induced MDD. Genetic studies reveal that neutral sphingomyelinase 2 is required for the formation of ceramide-enriched exosomes in the blood plasma. Accordingly, induced deficiency of neutral sphingomyelinase 2 prevented mice from the development of stress-induced MDD. Intravenous injection of microparticles from mice with MDD or injection of ceramide-loaded exosomes induced MDD-like behavior in untreated mice, which was abrogated by ex vivo pre-incubation of purified exosomes with anti-ceramide antibodies or ceramidase. Mechanistically, injection of exosomes from mice with MDD or injection of ex vivo ceramide-loaded microparticles inhibited phospholipase D (PLD) in endothelial cells in vitro and in the hippocampus in vivo and thereby decreased phosphatidic acid in the hippocampus, which has been previously shown to mediate MDD by plasma ceramide. In summary, our data indicate that ceramide-enriched exosomes are released by neutral sphingomyelinase 2 into the blood plasma upon stress and mediate stress-induced MDD. KEY MESSAGES: Stress induces ceramide-enriched exosomes in the blood plasma. Ceramide-enriched exosomes mediate major depressive disorder (MDD). Deficiency of neutral sphingomyelinase 2 protects from stress-induced MDD. Neutralization or digestion of ceramide in exosomes prevents stress-induced MDD. Ceramide-enriched exosomes inhibit endothelial phospholipase D in the hippocampus.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.