Stress induces major depressive disorder by a neutral sphingomyelinase 2-mediated accumulation of ceramide-enriched exosomes in the blood plasma

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.

The Role of Neutral Sphingomyelinase-2 (NSM2) in the Control of Neutral Lipid Storage in T Cells

“…It was shown previously that Cer negatively affected PLD activity [ 53 ]. In line with this, NSM2-generated Cer impaired PLD activity in mice models of major depressive disorder [ 8 ]. Published data on smpd3 −/− chondrocytes showed transcriptional upregulation of Golgi-associated SMS1 thereby affecting the NSM2-SMS1 cycle in the Golgi apparatus and DAG homeostasis [ 30 ].…”

“…Its usage of sphingomyelin (SM) as a substrate for the production of Cer at neutral pH was demonstrated more than a decade ago [ 7 ]. NSM2 mediates stress and inflammation induced Cer generation [ 8 , 9 , 10 ]. It is implicated in bone mineralization, growth arrest, apoptosis, and inflammation [ 11 , 12 ].…”

Sex, age, body mass index, and contraceptive use but not perceived stress influence healthy plasma lipidomic profiles

“…Ceramides were analyzed in detail per targeted and untargeted lipidomic analyses because previous studies have shown that ceramides in plasma are increased in mental disease [8,80], particularly major depression [81]. In mice, depression-like behavior occurs upon exposure to chronic unpredictable mils stress (CMUS) [82,83], which is one of the popular depression models and is associated with changes of ceramide metabolism via acidic sphingomyelinase which is believed to be triggered by stress [84] and may lead to depression [85]. The results of targeted and untargeted ceramide analyses were highly consistent (Figure 6 middle), but contrary to expectations, ceramides were not associated with perceived stress.…”

Characterization of a Neutral Sphingomyelinase Activity in Human Serum and Plasma

“…Due to its up to 20-fold higher expression in the brain compared to peripheral tissues [18], this enzyme could be of increased interest for neuroscience. Indeed, NSM-2 has been involved in the biogenesis of exosomes and the release of extracellular vesicles with relevance to many conditions, from cardiovascular [19] and cardiometabolic [20] diseases [19] to anxiety [21], major depressive disorder [22], and alcohol addiction [23,24]. While different tissue types are easily available from animal models, including brain regions, biological material from patients is mostly limited to peripheral liquid biopsies such as easily available blood, saliva, or urine samples, whereas tissue biopsies require more invasive procedures and may pose ethical problems.…”