Abstract
Sphingosine 1-phosphates (S1Ps) are bioactive lipids that mediate a diverse range of effects through the activation of cognate receptors, S1P1–S1P5. Scrutiny of S1P-regulated pathways over the past three decades has identified important and occasionally counteracting functions in the brain and cerebrovascular system. For example, while S1P1 and S1P3 mediate proinflammatory effects on glial cells and directly promote endothelial cell barrier integrity, S1P2 is anti-inflammatory but disrupts barrier integrity. Cumulatively, there is significant preclinical evidence implicating critical roles for this pathway in regulating processes that drive cerebrovascular disease and vascular dementia, both being part of the continuum of vascular cognitive impairment (VCI). This is supported by clinical studies that have identified correlations between alterations of S1P and cognitive deficits. We review studies which proposed and evaluated potential mechanisms by which such alterations contribute to pathological S1P signaling that leads to VCI-associated chronic neuroinflammation and neurodegeneration. Notably, S1P receptors have divergent but overlapping expression patterns and demonstrate complex interactions. Therefore, the net effect produced by S1P represents the cumulative contributions of S1P receptors acting additively, synergistically, or antagonistically on the neural, vascular, and immune cells of the brain. Ultimately, an optimized therapeutic strategy that targets S1P signaling will have to consider these complex interactions.
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Abbreviations
- AD:
-
Alzheimer’s disease
- ApoM:
-
Apolipoprotein M
- APP:
-
Amyloid precursor protein
- Aβ:
-
Beta-amyloid
- BACE1:
-
β-Secretase
- BBB:
-
Blood–brain barrier
- BCAS:
-
Bilateral carotid artery stenosis
- CAA:
-
Cerebral amyloid angiopathy
- CCAO:
-
Common carotid artery occlusion
- CeVD:
-
Cerebrovascular disease
- CNS:
-
Central nervous system
- CSF:
-
Cerebrospinal fluid
- ERK:
-
Extracellular signal-regulated kinase
- HDL:
-
High-density lipoprotein
- HIF:
-
Hypoxia-inducible factors
- HPC:
-
Hypoxic preconditioning
- ICH:
-
Intracerebral hemorrhage
- IL-1β:
-
Interleukin-1β
- IL-6:
-
Interleukin-6
- IL-8:
-
Interleukin-8
- iNOS:
-
Inducible nitric oxide synthase
- MMP-9:
-
Matrix metalloproteinase 9
- MS:
-
Multiple sclerosis
- NIHSS:
-
National Institute of Health stroke scores
- NPC:
-
Neural progenitor cells
- OGD:
-
Oxygen–glucose deprivation
- PLPP:
-
Lipid phosphate phosphatase
- S1P:
-
Sphingosine 1-phosphate
- S1P1 :
-
Sphingosine 1-phosphate receptor 1
- S1P2 :
-
Sphingosine 1-phosphate receptor 2
- S1P3 :
-
Sphingosine 1-phosphate receptor 3
- S1P4 :
-
Sphingosine 1-phosphate receptor 4
- S1P5 :
-
Sphingosine 1-phosphate receptor 5
- S1PR:
-
S1P receptors
- SGPL1:
-
S1P lyase
- SGPP:
-
Sphingosine 1-phosphate phosphatase
- SPHK:
-
Sphingosine kinase
- SPLIS:
-
S1P lyase insufficiency syndrome
- tMCAO:
-
Transient middle cerebral artery occlusion
- TNFα:
-
Tumor necrosis factor-alpha
- tPA:
-
Tissue plasminogen activator
- VaD:
-
Vascular dementia
- VCI:
-
Vascular cognitive impairment
- VSMC:
-
Vascular smooth muscle cells
- WML:
-
White matter lesions
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Acknowledgements
This work was supported by grants from the Ministry of Education, Singapore (R-181-000-183-114, WYO and DRH), the National University Health System, Singapore (NUHSRO/2019/051/T1/Seed-Mar/04, WYO and DRH), and the National Medical Research Council, Singapore (NMRC/CSA/CSA-SI/007/2016, CPC, MKPL, and DRH).
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Chua, X.Y., Ho, L.T.Y., Xiang, P. et al. Preclinical and Clinical Evidence for the Involvement of Sphingosine 1-Phosphate Signaling in the Pathophysiology of Vascular Cognitive Impairment. Neuromol Med 23, 47–67 (2021). https://doi.org/10.1007/s12017-020-08632-0
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DOI: https://doi.org/10.1007/s12017-020-08632-0