ArticleActa neuropathologica communications2014
Loss of the neuroprotective factor Sphingosine 1-phosphate early in Alzheimer's disease pathogenesis.
Article in Acta neuropathologica communications, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 93 papers.
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Who cites it
93 citing papers in PubMed, 164 citations in OpenAlex.
- Assessing the de novo paradigm in sporadic early-onset Alzheimer disease trios.Molecular psychiatry · 2026Article
- The Role of Sphingosine-1-Phosphate Signaling in Cerebral Ischemia/Reperfusion Injury and Alzheimer's Disease Pathology.International journal of molecular sciences · 2026Review
- Molecular mechanisms of exercise-induced improvements in Alzheimer's disease: a focus on lipid homeostasis.Translational neurodegeneration · 2026Review
- Fingolimod normalizes metabolic signatures associated with synaptic plasticity and memory in APP/PS1 model: Sphingosine-1-phosphate receptor a therapeutic target for Alzheimer's.Scientific reports · 2026Article
- The physiological and pathological effects of sphingolipid metabolism and signaling in the central nervous system.Brain pathology (Zurich, Switzerland) · 2026Review
- The novel sphingolipids cP1P and P1P attenuate neuroinflammation and enhance S1PR1/Akt/mTOR signaling to mitigate cognitive decline in an Alzheimer's disease mouse model.Cell communication and signaling : CCS · 2025Article
- Mechanisms of high-density lipoprotein in regulating blood-brain barrier function: insights and implications.Fluids and barriers of the CNS · 2025Review
- Regulation of presynaptic homeostatic plasticity by glial signalling in Alzheimer's disease.The Journal of physiology · 2025Review
- Stress Accelerates Depressive-Like Behavior through Increase of SPNS2 Expression in Tg2576 Mice.Biomolecules & therapeutics · 2025Article
- The sphingosine-1-phosphate signaling pathway (sphingosine-1-phosphate and its receptor, sphingosine kinase) and epilepsy.Epilepsia open · 2025Review
- Lipidome disruption in Alzheimer's disease brain: detection, pathological mechanisms, and therapeutic implications.Molecular neurodegeneration · 2025Review
- Rescue of hippocampal synaptic plasticity and memory performance by Fingolimod (FTY720) in APP/PS1 model of Alzheimer's disease is accompanied by correction in metabolism of sphingolipids, polyamines, and phospholipid saturation composition.bioRxiv : the preprint server for biology · 2025Article
- Deciphering the role of sphingosine 1-phosphate in central nervous system myelination and repair.Journal of neurochemistry · 2025Review
- Phospholipidomics in Clinical Trials for Brain Disorders: Advancing our Understanding and Therapeutic Potentials.Molecular neurobiology · 2024Review
- Density of Sphingosine-1-Phosphate Receptors Is Altered in Cortical Nerve-Terminals of Insulin-Resistant Goto-Kakizaki Rats and Diet-Induced Obese Mice.Neurochemical research · 2024Article
- Frontal Cortex Lipid Alterations During the Onset of Alzheimer's Disease.Journal of Alzheimer's disease : JAD · 2024Article
- The Effect of FTY720 on Sphingolipid Imbalance and Cognitive Decline in Aged EFAD Mice.Journal of Alzheimer's disease reports · 2024Article
- Alzheimer's disease manifests abnormal sphingolipid metabolism.Frontiers in aging neuroscience · 2024Article
- Glial Sphingosine-Mediated Epigenetic Regulation Stabilizes Synaptic Function inThe Journal of neuroscience : the official journal of the Society for Neuroscience · 2023Article
- Article
33 more citing papers are in PubMed but not listed here.
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10 authors at 4 institutions in 1 country.
Funding
Abstract
backgroundThe greatest genetic risk factor for late-onset Alzheimer's disease (AD) is the ϵ4 allele of Apolipoprotein E (ApoE). ApoE regulates secretion of the potent neuroprotective signaling lipid Sphingosine 1-phosphate (S1P). S1P is derived by phosphorylation of sphingosine, catalysed by sphingosine kinases 1 and 2 (SphK1 and 2), and SphK1 positively regulates glutamate secretion and synaptic strength in hippocampal neurons. S1P and its receptor family have been subject to intense pharmacological interest in recent years, following approval of the immunomodulatory drug Fingolimod, an S1P mimetic, for relapsing multiple sclerosis.
resultsWe quantified S1P levels in six brain regions that are differentially affected by AD pathology, in a cohort of 34 post-mortem brains, divided into four groups based on Braak neurofibrillary tangle staging. S1P declined with increasing Braak stage, and this was most pronounced in brain regions most heavily affected by AD pathology. The S1P/sphingosine ratio was 66% and 64% lower in Braak stage III/IV hippocampus (p = 0.010) and inferior temporal cortex (p = 0.014), respectively, compared to controls. In accordance with this change, both SphK1 and SphK2 activity declined with increasing Braak pathology in the hippocampus (p = 0.032 and 0.047, respectively). S1P/sphingosine ratio was 2.5-fold higher in hippocampus of ApoE2 carriers compared to ApoE4 carriers, and multivariate regression showed a significant association between APOE genotype and hippocampal S1P/sphingosine (p = 0.0495), suggesting a new link between APOE genotype and pre-disposition to AD.
conclusionsThis study demonstrates loss of S1P and sphingosine kinase activity early in AD pathogenesis, and prior to AD diagnosis. Our findings establish a rationale for further exploring S1P receptor pharmacology in the context of AD therapy.
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