Dysregulation of sphingosine-1-phosphate (S1P) and S1P receptor 1 signaling in the 5xFAD mouse model of Alzheimer’s disease

Jung, Younghun; Lopez-Benitez, Jonathan; Tognoni, Christina M.; Carreras, Isabel; Dedeoglu, Alpaslan

doi:10.1016/j.brainres.2022.148171

Cited by 16 publications

(5 citation statements)

References 85 publications

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“… 49 Recently, S1PR1 protein levels were shown to be upregulated in 8- and 14-month-old 5XFAD brain cortex, which is consistent with the results in our study. 50 While Aβ 42 was shown to directly affect or even bind to TLR4, it was not clear how Aβ 42 increased the level of S1PR1. While Ponesimod is a highly specific functional antagonist of S1PR1, it was not clear how Ponesimod prevented the Aβ 42 -induced increase of TLR4.…”

Section: Discussionmentioning

confidence: 99%

The S1P receptor 1 antagonist Ponesimod reduces TLR4-induced neuroinflammation and increases Aβ clearance in 5XFAD mice

et al. 2023

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Section: Discussionmentioning

confidence: 99%

The S1P receptor 1 antagonist Ponesimod reduces TLR4-induced neuroinflammation and increases Aβ clearance in 5XFAD mice

et al. 2023

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“…Compared to the distribution of the activity of other receptors for neurolipids such as the CB 1 cannabinoid receptor, the cortical activity of the S1P 1 receptor was even higher, but its distribution was similar (Herkenham et al, 1991; Sim et al, 1996). In this regard, the S1P system is regulated in both patient cortex and animal models of Alzheimer’s disease, such as 5xFAD, suggesting the relevance of this system in cognitive degeneration (Couttas et al, 2014; Jung et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

Localization of S1P₁Receptor Signaling in the rat, mouse and human Central Nervous System

Martínez-Gardeazabal,

Pereira-Castelo,

Moreno-Rodríguez

et al. 2024

Preprint

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Some specific lipid molecules present in the brain are signaling molecules at the intracellular compartments or behaving as neurotransmitters or neuromodulators of other systems, binding to specific G protein-coupled receptors (GPCR) for neurolipids. One of these receptors is the sphingosine 1-phosphate receptor subtype 1, coupled to Gi/o-proteins and involved in cell proliferation, growth or neuroprotection. Thus, an interesting target for neurodegenerative diseases, such as Alzheimers. The present study compares the human cerebral distribution of the activity mediated by S1P1 receptor with the that in the brain of rodent experimental models, rat and mice by functional autoradiography, measuring the [35S]GTPyS binding stimulated by the S1P1 receptor selective agonist CYM-5442 to get the anatomy of the S1P1 receptor activity. The S1P1 receptor-mediated activity is, together with that of the CB1 cannabinoid receptor, one of the highest recorded for any GPCR in most of the grey matter areas of the brain, reaching up to 50%-500% over basal, depending on the agonist and brain area. The S1P1 receptor signaling is very relevant in those areas that regulate learning and memory processes, such as the basal forebrain, but also in others involved in control of motor processes or nociception e.g. basal ganglia. The results also reveal that the rat would be a preferable experimental model to extrapolate for the S1P1 receptor-mediated responses in human brain.

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“…Although the above-mentioned studies have demonstrated that SPL may regulate APP metabolism, there are also experiments indicating the opposite, i.e., increased SPL level as a result of enhanced APP or Aβ level. An advantage of the S1P degrading enzyme over S1P kinases was observed in the brain cortex of five familial Alzheimer’s disease (5xFAD) transgenic mice aged 8 and 14 months but not in 3-month-old individuals [ 93 ]. Furthermore, disturbed S1P metabolism was accompanied by increased S1PR1 level and enhanced activity of its downstream Akt/mTor/Tau signaling pathway in aging animals.…”

Section: Spl In Neurodegenerative Diseasesmentioning

confidence: 99%

“…Furthermore, disturbed S1P metabolism was accompanied by increased S1PR1 level and enhanced activity of its downstream Akt/mTor/Tau signaling pathway in aging animals. In all groups, an increased level of APP was observed [ 93 ]. A higher protein level of SPL, together with an enhanced protein level of S1PP and a decreased level of SphK2, was also demonstrated in a model of memory deficit induced by intrahippocampal Aβ injection [ 94 ].…”

Section: Spl In Neurodegenerative Diseasesmentioning

confidence: 99%

Recent Insight into the Role of Sphingosine-1-Phosphate Lyase in Neurodegeneration

Wieczorek

Strosznajder

2023

IJMS

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Sphingosine-1-phosphate lyase (SPL) is a pyridoxal 5′-phosphate-dependent enzyme involved in the irreversible degradation of sphingosine-1-phosphate (S1P)—a bioactive sphingolipid that modulates a broad range of biological processes (cell proliferation, migration, differentiation and survival; mitochondrial functioning; and gene expression). Although SPL activity leads to a decrease in the available pool of S1P in the cell, at the same time, hexadecenal and phosphoethanolamine, compounds with potential biological activity, are generated. The increased expression and/or activity of SPL, and hence the imbalance between S1P and the end products of its cleavage, were demonstrated in several pathological states. On the other hand, loss-of-function mutations in the SPL encoding gene are a cause of severe developmental impairments. Recently, special attention has been paid to neurodegenerative diseases as the most common pathologies of the nervous system. This review summarizes the current findings concerning the role of SPL in the nervous system with an emphasis on neurodegeneration. Moreover, it briefly discusses pharmacological compounds directed to inhibit its activity.

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Dysregulation of sphingosine-1-phosphate (S1P) and S1P receptor 1 signaling in the 5xFAD mouse model of Alzheimer’s disease

Cited by 16 publications

References 85 publications

The S1P receptor 1 antagonist Ponesimod reduces TLR4-induced neuroinflammation and increases Aβ clearance in 5XFAD mice

The S1P receptor 1 antagonist Ponesimod reduces TLR4-induced neuroinflammation and increases Aβ clearance in 5XFAD mice

Localization of S1P₁Receptor Signaling in the rat, mouse and human Central Nervous System

Recent Insight into the Role of Sphingosine-1-Phosphate Lyase in Neurodegeneration

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Dysregulation of sphingosine-1-phosphate (S1P) and S1P receptor 1 signaling in the 5xFAD mouse model of Alzheimer’s disease

Cited by 16 publications

References 85 publications

The S1P receptor 1 antagonist Ponesimod reduces TLR4-induced neuroinflammation and increases Aβ clearance in 5XFAD mice

The S1P receptor 1 antagonist Ponesimod reduces TLR4-induced neuroinflammation and increases Aβ clearance in 5XFAD mice

Localization of S1P1Receptor Signaling in the rat, mouse and human Central Nervous System

Recent Insight into the Role of Sphingosine-1-Phosphate Lyase in Neurodegeneration

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Localization of S1P₁Receptor Signaling in the rat, mouse and human Central Nervous System