Ceramide levels in blood plasma correlate with major depressive disorder severity and its neutralization abrogates depressive behavior in mice

Schumacher F, Edwards MJ, Mühle C, Carpinteiro A, Wilson GC, Wilker B, Soddemann M, Keitsch S, Scherbaum N, Müller BW, Lang UE, Linnemann C, Kleuser B, Müller CP, Kornhuber J, Gulbins E (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Journal of Biological Chemistry American Society for Biochemistry and Molecular Biology

Book Volume: 298

Article Number: 102185

Journal Issue: 8

DOI: 10.1016/j.jbc.2022.102185

Abstract

Major depressive disorder (MDD) is a severe disease of unknown pathogenesis that will affect ∼10% of people during their lifetime. Therapy for MDD requires prolonged treatment and often fails, predicating a need for novel treatment strategies. Here, we report increased ceramide levels in the blood plasma of MDD patients and in murine stress-induced models of MDD. These blood plasma ceramide levels correlated with the severity of MDD in human patients and were independent of age, sex, or body mass index. In addition, intravenous injection of anti-ceramide antibodies or neutral ceramidase rapidly abrogated stress-induced MDD, and intravenous injection of blood plasma from mice with MDD induced depression-like behavior in untreated mice, which was abrogated by ex vivo preincubation of the plasma with anti-ceramide antibodies or ceramidase. Mechanistically, we demonstrate that ceramide accumulated in endothelial cells of the hippocampus of stressed mice, evidenced by the quantitative measurement of ceramide in purified hippocampus endothelial cells. We found ceramide inhibited the activity of phospholipase D (PLD) in endothelial cells in vitro and in the hippocampus in vivo and thereby decreased phosphatidic acid in the hippocampus. Finally, we show intravenous injection of PLD or phosphatidic acid abrogated MDD, indicating the significance of this pathway in MDD pathogenesis. Our data indicate that ceramide controls PLD activity and phosphatidic acid formation in hippocampal endothelial cells and thereby mediates MDD. We propose that neutralization of plasma ceramide could represent a rapid-acting targeted treatment for MDD.

Authors with CRIS profile

Christiane Mühle Department of Psychiatry and Psychotherapy Peter Christian Müller Professur für Suchtmedizin Johannes Kornhuber Lehrstuhl für Psychiatrie und Psychotherapie

Involved external institutions

Universitätsklinikum Essen DE Germany (DE) University of Cincinnati US United States (USA) (US) Universität Duisburg-Essen (UDE) DE Germany (DE) Universitäre Psychiatrische Kliniken Basel (UPK) / Universitäre Psychiatrische Kliniken Base CH Switzerland (CH) Freie Universität Berlin DE Germany (DE)

How to cite

APA:

Schumacher, F., Edwards, M.J., Mühle, C., Carpinteiro, A., Wilson, G.C., Wilker, B.,... Gulbins, E. (2022). Ceramide levels in blood plasma correlate with major depressive disorder severity and its neutralization abrogates depressive behavior in mice. Journal of Biological Chemistry, 298(8). https://doi.org/10.1016/j.jbc.2022.102185

MLA:

Schumacher, Fabian, et al. "Ceramide levels in blood plasma correlate with major depressive disorder severity and its neutralization abrogates depressive behavior in mice." Journal of Biological Chemistry 298.8 (2022).

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