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Mol Neurobiol. 2019 Aug;56(8):5436-5455. doi: 10.1007/s12035-018-1448-3. Epub 2019 Jan 5.

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

Author information

1
Laboratory of Preclinical Research and Environmental Agents, Department of Neurosurgery, M. Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego St., PL-02106, Warsaw, Poland.
2
Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego St., PL-02106, Warsaw, Poland.
3
LSU Neuroscience Center and Departments of Neurology and Ophthalmology, Louisiana State University School of Medicine, New Orleans, LA, 70112, USA.
4
Laboratory of Preclinical Research and Environmental Agents, Department of Neurosurgery, M. Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego St., PL-02106, Warsaw, Poland. rstrosznajder@imdik.pan.pl.

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.

KEYWORDS:

Alzheimer’s disease; Ceramide; Huntington’s disease; Parkinson’s disease; Sphingosine-1-phosphate; microRNA

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