The Role of Ceramide and Sphingosine-1-Phosphate in Alzheimer’s Disease and Other Neurodegenerative Disorders

Abstract

Bioactive sphingolipids—ceramide, sphingosine, and their respective 1-phosphates (C1P and S1P)—are signaling molecules serving as intracellular second messengers. Moreover, S1P acts through G protein-coupled receptors in the plasma membrane. Accumulating evidence points to sphingolipids' engagement in brain aging and in neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Huntington’s diseases and amyotrophic lateral sclerosis. Metabolic alterations observed in the course of neurodegeneration favor ceramide-dependent pro-apoptotic signaling, while the levels of the neuroprotective S1P are reduced. These trends are observed early in the diseases’ development, suggesting causal relationship. Mechanistic evidence has shown links between altered ceramide/S1P rheostat and the production, secretion, and aggregation of amyloid β/α-synuclein as well as signaling pathways of critical importance for the pathomechanism of protein conformation diseases. Sphingolipids influence multiple aspects of Akt/protein kinase B signaling, a pathway that regulates metabolism, stress response, and Bcl-2 family proteins. The cross-talk between sphingolipids and transcription factors including NF-κB, FOXOs, and AP-1 may be also important for immune regulation and cell survival/death. Sphingolipids regulate exosomes and other secretion mechanisms that can contribute to either the spread of neurotoxic proteins between brain cells, or their clearance. Recent discoveries also suggest the importance of intracellular and exosomal pools of small regulatory RNAs in the creation of disturbed signaling environment in the diseased brain. The identified interactions of bioactive sphingolipids urge for their evaluation as potential therapeutic targets. Moreover, the early disturbances in sphingolipid metabolism may deliver easily accessible biomarkers of neurodegenerative disorders.

LC-HRMS based approach to identify novel sphingolipid biomarkers in breast cancer patients

“…An earlier report suggested that high ceramide levels are associated with low proliferation potency in breast cancer patients 24 . Although, ceramide phosphates are formed from the ceramides, the two metabolites have antagonistic effects in cancer 25,26 . The present study is the first report on the levels of ceramide phosphates and CERK expression in breast cancer patients and clinical correlations of ceramide phosphates with Ki67 index, making it a pioneer study in this field.…”

Lysophospholipids and Their G-Coupled Protein Signaling in Alzheimer’s Disease: From Physiological Performance to Pathological Impairment

“…Similarly, five S1P receptors (S1PR1-5) belonging to the Edg family engage in the regulation of cellular biological events through G q , G i , G 12/13 , and Rho proteins Czubowicz et al, 2019). S1P with specific high-affinity S1PRs, have multiple ancillary roles in the regulation of oxidative stress (Sinha et al, 2013;Pyszko and Strosznajder, 2014), apoptosis (Edsall et al, 1997;Ghasemi et al, 2016), mitochondrial dysfunction (Chan and Pitson, 2013;Santos and Lynch, 2015;Ghasemi et al, 2016), autophagy (Moruno Manchon et al, 2015) and neuronal development (Mizugishi et al, 2005;Hait et al, 2014;Ghasemi et al, 2016).…”

Sphingosine-1-Phosphate (S-1P) Promotes Differentiation of Naive Macrophages and Enhances Protective Immunity Against Mycobacterium tuberculosis

“…Sphingolipids are active constituents of the mucus secreted by alveolar epithelium and protects the lung tissue from invading pathogens. Out of various sphingolipid metabolites, sphingosine-1-phosphate (S-1P), and ceramide are the best studied sphingolipids in the context of various respiratory pathologies (8)(9)(10). As S-1P and ceramide were known to exert opposite signaling in the host (11,12), S-1P/ceramide rheostat would be a decisive parameter in predicting how cells would respond differentially to the same stimuli during disease progression.…”