Neuronal sphingosine kinase 2 subcellular localization is altered in Alzheimer’s disease brain

Abstract

BackgroundAlzheimer’s disease (AD) is characterized by the accumulation of β-amyloid (Aβ) peptides and hyperphosphorylated tau protein accompanied by neuronal loss. Aβ accumulation has been associated with an impaired sphingosine 1-phosphate (S1P) metabolism. S1P is generated by sphingosine kinases (SphKs), of which there are two isoenzymes SphK1 and SphK2, and degraded by the sphingosine 1-phosphate lyase (SPL). We previously reported, that both a decrease in SphK1 expression and an increase in SPL expression, correlated with amyloid deposits in the entorhinal cortex of AD brains, suggesting a global loss of pro-survival S1P in AD neurons. SphK2 contribution has also been examined in AD yielding to conflicting results that may reflect the complexity of SphK2 regulation. The subcellular localization of SphK2, hence the compartmentalization of generated S1P, is recognized to play a crucial role in dictating either its pro-survival or pro-apoptotic functions. We therefore aimed at studying the expression of SphK2 and notably its subcellular localization in brain tissues from patients with AD.ResultsWe report that a decrease in SphK2 protein cytosolic expression correlated with the density of amyloid deposits in a cohort of 25 post-mortem brains. Interestingly, we observed that the equilibrium between cytoplasmic and nuclear SphK2 is disrupted and showed that SphK2 is preferentially localized in the nucleus in AD brain extracts as compared to control extracts, with a marked increase of cleaved SphK2.ConclusionsOur results suggest that a shift in the subcellular localization of the S1P generating SphK2 may compromise the well established pro-survival cytosolic S1P by favoring the production of nuclear S1P associated with adverse effects in AD pathogenesis.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0527-z) contains supplementary material, which is available to authorized users.

Sphingosine Kinase 2 Potentiates Amyloid Deposition but Protects against Hippocampal Volume Loss and Demyelination in a Mouse Model of Alzheimer's Disease

“…We speculate that loss of SK2 function and S1P in AD is attributed to the altered lipid environment of endosomal membranes. This could impair SK2 recruitment to endosomes, a possibility that will be investigated in future studies, and may explain redistribution of SK2 from cytosol to nucleus in neurons of AD brains (Dominguez et al, 2018). SK2 deficiency abated hippocampal epileptiform activity in J20 mice, supporting prior research showing that this hyperexcitatory activity is A␤-dependent (Verret et al, 2012;A.…”

“…S1P loss was statistically significant at Braak stages III-IV, corresponding to a pre-AD neuropathological state (Braak and Braak, 1995). He et al (2010) showed loss of S1P in AD frontal cortex, whereas another study showed reduced cytosolic and increased nuclear SK2 in AD (Dominguez et al, 2018). We have also shown an inverse correlation between S1P levels and age in the hippocampus of cognitively normal females (Couttas et al, 2018), suggesting that loss of neuroprotective S1P may sensitize to neurodegeneration.…”

Lysophospholipids and Their G-Coupled Protein Signaling in Alzheimer’s Disease: From Physiological Performance to Pathological Impairment

“…Several lines of evidence have suggested that there is an increase in SphK2 activity in the frontal cortex while SphK2 expression inhibition was observed in the temporal cortex and hippocampus of AD brains (Takasugi et al, 2011;Maceyka et al, 2012;Asle-Rousta et al, 2013). Dominguez et al (2018) have demonstrated the re-localization of SphK2 from the cytosol to the nucleus relative to Aβ pathology, leading to the upregulation of intranuclear S1P expression as well as a series of deleterious responses. This is following the evidence that S1P functions by indirectly modulating β-site APP cleaving enzyme-1 (β-secretase, BACE1), which is considered as the rate-limiting enzyme for amyloid-β peptide (Aβ) production (Takasugi et al, 2011;Maceyka et al, 2012).…”

Does Siponimod Exert Direct Effects in the Central Nervous System?

“…Beyond, the activities of lipid phosphate phosphohydrolase 3 (LPP3), also known as phospholipid phosphatase 3 (PLPP3) or sphingosine-1-phosphate phosphohydrolase (SPP1), can convert FTY720-P into its inactive, dephosphorylated metabolites [100] and, thus, reverse the mechanism actions from Sphk2. In several studies, the dynamic regulation of sphingosine kinases and phosphatases was observed in some disease models such as Alzheimer's [101] or brain tumors [102]. To what extent the expression of these enzymes changes in MS and how this may affect the therapeutic efficacy of fingolimod remains to be determined.…”