Preclinical and Clinical Evidence for the Involvement of Sphingosine 1-Phosphate Signaling in the Pathophysiology of Vas
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REVIEW PAPER
Preclinical and Clinical Evidence for the Involvement of Sphingosine 1‑Phosphate Signaling in the Pathophysiology of Vascular Cognitive Impairment Xin Ying Chua1 · Leona T. Y. Ho2 · Ping Xiang1 · Wee Siong Chew1 · Brenda Wan Shing Lam1 · Christopher P. Chen1,3 · Wei‑Yi Ong2,4 · Mitchell K. P. Lai1,3 · Deron R. Herr1,5,6 Received: 26 September 2020 / Accepted: 3 November 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Sphingosine 1-phosphates (S1Ps) are bioactive lipids that mediate a diverse range of effects through the activation of cognate receptors, S 1P1–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 S 1P1 and S1P3 mediate proinflammatory effects on glial cells and directly promote endothelial cell barrier integrity, S 1P2 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. Keywords Lipid signaling · Dementia · Alzheimer’s disease · Cerebrovascular disease · Stroke · Sphingolipids · Ceramide
* Mitchell K. P. Lai [email protected] * Deron R. Herr [email protected] 1
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
2
Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119260, Singapore
3
Memory Aging and Cognition Centre, National University Health System, Kent Ridge, Singapore
4
Neurobiology Programme, Life Sciences Institute, National University of Singapore, Singapore 119260, Singapore
5
Department of Biology, San Diego State University, San Diego, CA, USA
6
American University of Health Sciences, Long Beach, CA, USA
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 c
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