Targeted lipidomics reveal derangement of ceramides in major depression and bipolar disorder

Brunkhorst-Kanaan, Nathalie; Klatt-Schreiner, Katharina; Hackel, J.; Schröter, Katrin; Trautmann, Sandra; Hahnefeld, Lisa; Wicker, Sabine; Reif, Andreas; Thomas, Dominique; Geißlinger, Gerd; Kittel‐Schneider, Sarah; Tegeder, Irmgard

doi:10.1016/j.metabol.2019.04.002

Cited by 84 publications

(89 citation statements)

References 55 publications

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“…Similarly, plasma levels of several ceramide species, including Cer16:0, Cer18:0, Cer20:0, Cer24:1, and Cer26:1 but not Cer22:0 or Cer24:0, were increased in patients experiencing a major depressive episode during the past 2 years [9]. Higher plasma ceramide Cer16:0, Cer18:0, Cer20:0, Cer22:0, Cer24:0, and Cer24:1 levels were also observed in patients with MDD and bipolar disorder [10], and higher plasma levels of ceramide Cer16:0 and Cer18:0 and sphingomyelin SM18:1 were associated with the increased severity of depression symptoms in patients with coronary artery disease [11]. In contrast, plasma sphingomyelin SM26:1 [12], SM21:0 and SM21:1 [13] levels were decreased in MDD patients, and the SM23:1/SM16:0 ratio was negatively correlated with the severity of depressive symptoms in a Dutch family [14].…”

Section: Introductionmentioning

confidence: 86%

The Forebrain-Specific Overexpression of Acid Sphingomyelinase Induces Depressive-Like Symptoms in Mice

Zoicas

Schumacher

Kleuser

et al. 2020

Cells

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Human and murine studies identified the lysosomal enzyme acid sphingomyelinase (ASM) as a target for antidepressant therapy and revealed its role in the pathophysiology of major depression. In this study, we generated a mouse model with overexpression of Asm (Asm-tgfb) that is restricted to the forebrain to rule out any systemic effects of Asm overexpression on depressive-like symptoms. The increase in Asm activity was higher in male Asm-tgfb mice than in female Asm-tgfb mice due to the breeding strategy, which allows for the generation of wild-type littermates as appropriate controls. Asm overexpression in the forebrain of male mice resulted in a depressive-like phenotype, whereas in female mice, Asm overexpression resulted in a social anxiogenic-like phenotype. Ceramides in male Asm-tgfb mice were elevated specifically in the dorsal hippocampus. mRNA expression analyses indicated that the increase in Asm activity affected other ceramide-generating pathways, which might help to balance ceramide levels in cortical brain regions. This forebrain-specific mouse model offers a novel tool for dissecting the molecular mechanisms that play a role in the pathophysiology of major depression.

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Section: Introductionmentioning

confidence: 86%

The Forebrain-Specific Overexpression of Acid Sphingomyelinase Induces Depressive-Like Symptoms in Mice

Zoicas

Schumacher

Kleuser

et al. 2020

Cells

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“…Lipid analyses were done using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS), according to procedures we have developed and described in e.g. 91,99,100 , recent updates in 101,102 . Plasma sample (100 μl) or tissue homogenates were extracted by liquid-liquid-extraction using two cycles of ethyl acetate: n-hexane (9:1, v/v) after spiking them with the corresponding internal standards (deuterated analytes).…”

Section: Analysis Of Endocannabinoidsmentioning

confidence: 99%

Low brain endocannabinoids associated with persistent non-goal directed nighttime hyperactivity after traumatic brain injury in mice

Vogel

Wilken-Schmitz

Hummel

et al. 2020

Sci Rep

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Traumatic brain injury (TBI) is a frequent cause of chronic headache, fatigue, insomnia, hyperactivity, memory deficits, irritability and posttraumatic stress disorder. Recent evidence suggests beneficial effects of pro-cannabinoid treatments. We assessed in mice levels of endocannabinoids in association with the occurrence and persistence of comparable sequelae after controlled cortical impact in mice using a set of long-term behavioral observations in IntelliCages, motor and nociception tests in two sequential cohorts of TBI/sham mice. TBI mice maintained lower body weights, and they had persistent low levels of brain ethanolamide endocannabinoids (eCBs: AEA, OEA, PEA) in perilesional and subcortical ipsilateral brain tissue (6 months), but rapidly recovered motor functions (within days), and average nociceptive responses were within normal limits, albeit with high variability, ranging from loss of thermal sensation to hypersensitivity. TBI mice showed persistent non-goal directed nighttime hyperactivity, i.e. they visited rewarding and non-rewarding operant corners with high frequency and random success. On successful visits, they made more licks than sham mice resulting in net over-licking. The lower the eCBs the stronger was the hyperactivity. In reward-based learning and reversal learning tasks, TBI mice were not inferior to sham mice, but avoidance memory was less stable. Hence, the major late behavioral TBI phenotype was non-goal directed nighttime hyperactivity and "over-licking" in association with low ipsilateral brain eCBs. The behavioral phenotype would agree with a "post-TBI hyperactivity disorder". The association with persistently low eCBs in perilesional and subcortical regions suggests that eCB deficiency contribute to the post-TBI psychopathology.

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“…Spatial and temporal lipid homeostasis is a tightly regulated process, and increasing evidence for aberrant lipid metabolism due to the dysregulation of homeostatic mechanisms has been linked to metabolic diseases, such as diabetes [6], the lysomal storage disorder Niemann-Pick disease type C [7], as well as neurological disorders including major depression, bipolar disorder [8], schizophrenia [9], and a range of neurodegenerative disorders including Parkinson's disease [10], dementia with Lewy bodies [11], and Alzheimer's disease (AD); the focus of the research presented herein.…”

Section: Introductionmentioning

confidence: 99%

Brain region–specific lipid alterations in the PLB4 hBACE1 knock-in mouse model of Alzheimer’s disease

et al. 2020

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Background: Lipid dysregulation is associated with several key characteristics of Alzheimer's disease (AD), including amyloid-β and tau neuropathology, neurodegeneration, glucose hypometabolism, as well as synaptic and mitochondrial dysfunction. The β-site amyloid precursor protein cleavage enzyme 1 (BACE1) is associated with increased amyloidogenesis, and has been affiliated with diabetes via its role in metabolic regulation. Methods: The research presented herein investigates the role of hBACE1 in lipid metabolism and whether specific brain regions show increased vulnerability to lipid dysregulation. By utilising advanced mass spectrometry techniques, a comprehensive, quantitative lipidomics analysis was performed to investigate the phospholipid, sterol, and fatty acid profiles of the brain from the well-known PLB4 hBACE1 knock-in mouse model of AD, which also shows a diabetic phenotype, to provide insight into regional alterations in lipid metabolism. Results: Results show extensive regionspecific lipid alterations in the PLB4 brain compared to the wild-type, with decreases in the phosphatidylethanolamine content of the cortex and triacylglycerol content of the hippocampus and hypothalamus, but increases in the phosphatidylcholine, phosphatidylinositol, and diacylglycerol content of the hippocampus. Several sterol and fatty acids were also specifically decreased in the PLB4 hippocampus. Conclusion: Collectively, the lipid alterations observed in the PLB4 hBACE1 knock-in AD mouse model highlights the regional vulnerability of the brain, in particular the hippocampus and hypothalamus, to lipid dysregulation, hence supports the premise that metabolic abnormalities have a central role in both AD and diabetes.

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Targeted lipidomics reveal derangement of ceramides in major depression and bipolar disorder

Cited by 84 publications

References 55 publications

The Forebrain-Specific Overexpression of Acid Sphingomyelinase Induces Depressive-Like Symptoms in Mice

The Forebrain-Specific Overexpression of Acid Sphingomyelinase Induces Depressive-Like Symptoms in Mice

Low brain endocannabinoids associated with persistent non-goal directed nighttime hyperactivity after traumatic brain injury in mice

Brain region–specific lipid alterations in the PLB4 hBACE1 knock-in mouse model of Alzheimer’s disease

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