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Review
, 56 (8), 5436-5455

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

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Review

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

Kinga Czubowicz et al. Mol Neurobiol.

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.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1. Signaling pathways triggered by the cell surface receptors for S1P (S1PRs) and C1P (C1PR).
S1P through its G protein-binding receptors modulates pathways known for their engagement in the regulation of cellular metabolism oxidative/nitrosative stress and death/survival. The depicted examples of S1PR-activated signaling pathways are far from exhausting the spectrum of observed interactions (e.g., S1PR2 inhibits Akt while S1PR3 activates it; iNOS is typically induced by NF-κB, but can also undergo S1P-/C1P-dependent suppression via p38 MAPK [8, 33]). In contrast, C1PR, the cell surface receptor for ceramide-1-phosphate, remains poorly characterized and it is generally not known what part of C1P effects it mediates. According to [34], modified
Fig. 2
Fig. 2. The changes in bioactive sphingolipid levels observed in aging and neurodegenerative disorders.
Numerous observations in postmortem brain tissues point to the imbalance in the ratio between the concentrations of the apoptosis inducer ceramide, and the typically anti-apoptotic S1P (see Pts. 'Bioactive Sphingolipids in the Pathomechanism of Alzheimer’s Disease' and 'The Role of Bioactive Sphingolipids in Parkinson’s Disease'). Much fewer works address the problem of physiological brain aging, where the changes appear to be partially gender-specific [44].The asterisk indicates clinical data about S1P in PD is missing; however, in experimental disease models, reduced SPHK activity leading to loss of Akt signaling was observed [45, 46].
Fig. 3
Fig. 3. The role of ceramide and S1P in neurodegeneration pathways.
a Ceramide-induced axon loss and neuronal apoptosis. According to [37], modified. b The roles of S1P and SPHKs in the modulation of neuronal death. According to various authors (see text). Both S1P and ceramide(s) exert major part of their opposing influence on cell survival through multi-level modulation of the PI3K–Akt pathway, which integrates sphingolipid-based signals with clues on the metabolic condition of the cell, stress levels, etc. [8, 37, 47]. Moreover, sphingolipid signaling displays links with the transcription factors AP-1 and NF-κB [–52], which regulate a plethora of processes including cell death and inflammation. Akt targets FOXO1a, 3a, 4, and 6 are engaged in cell death regulation in human tissues [53, 54]. The prevailing role of elevated ceramide in cell degeneration/death is mediated by multiple signals: inhibition of mitochondrial respiration and increased production of reactive oxygen species [55]; the release of AIF, cytochrome c, or SMAC from mitochondria; the Bcl-2-binding protein beclin1; autophagosomal LC3-II (which binds mitochondrial ceramide to induce lethal mitophagy) [–58]. While inhibition of HDAC1 and -2 is engaged in the pro-survival signaling of S1P, the role of HDAC3 is more ambiguous [–62]. AIF, apoptosis-inducing factor; AP-1, activator protein-1; aSMase, acid SMase; LC3-II, lipidated microtubule-associated protein 1 light chain 3β; C1P, ceramide-1-phosphate; C1PP, C1P phosphatase; CERS, ceramide synthase; DEGS, dihydroceramide desaturase; ERK, extracellular signal-regulated kinase; FOXO, forkhead box protein O; GSK-3β, glycogen synthase kinase 3β; HDAC, histone deacetylase; Jnk, c-Jun N-terminal kinase; MRC, mitochondrial respiratory chain; NF-κB, nuclear factor κB; PI3K, phosphoinositide 3-kinase; PP2A, protein phosphatase 2A; ROS, reactive oxygen species; S1P, sphingosine-1-phosphate; S1PR, S1P receptors; SMAC, second mitochondria-derived activator of caspases; SMase, sphingomyelinase; SPHK, sphingosine kinase; SPT, serine palmitoyltransferase; TRAF2, TNF receptor-associated factor 2
Fig. 4
Fig. 4. Changes in brain sphingolipid metabolism and signaling observed in Alzheimer’s disease.
Human postmortem brain material was used by numerous authors to compare the levels of bioactive sphingolipids, mRNAs, proteins, and enzyme activities. In the hippocampus S1P levels, mRNAs for CERK, S1PR1, SPHK1, SPHK2, and SPHK activity are reduced [65, 147, 148]. Lower S1P levels, S1PR1 protein, and SPHK protein/activities were observed along elevated S1P lyase proteins in selected cortical areas and in the hippocampus [65, 144]. Increased ceramide (Cer) and sphingomyelin (SM) levels, mRNAs for ceramide synthases (CERS1, 2), SGPL1, SPTLC2, aSMase, and sphingomyelinase protein and activity were observed in brain cortical areas, while ASAH1, CERK, and CERS6 mRNAs were reduced [–151]
Fig. 5
Fig. 5. Changes in brain sphingolipid metabolism/signaling observed in Parkinson’s disease and its experimental models.
Ceramide synthase (CERS) mRNAs, ceramide (Cer), and sphingomyelin (SM) species were measured in postmortem PD brains by Abbott et al. Increased CERS1 expression was found along with a shift towards shorter ceramide acyl chain lengths in brain regions most affected by the disease, although reduction in total levels of ceramide and sphingomyelin concentration was observed [192]. Reduced sphingosine kinase-1 and -2 (SPHKs) and S1P receptor 1 (S1PR1) expression was observed in the mouse MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced model [46, 193]. The MPTP model also displayed lower protein levels and activity of SPHK1 [193, 194]

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