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

Abstract

Sphingosine 1-phosphate (S1P) is a potent vasculoprotective and neuroprotective signaling lipid, synthesized primarily by sphingosine kinase 2 (SK2) in the brain. We have reported pronounced loss of S1P and SK2 activity early in Alzheimer's disease (AD) pathogenesis, and an inverse correlation between hippocampal S1P levels and age in females, leading us to speculate that loss of S1P is a sensitizing influence for AD. Paradoxically, SK2 was reported to mediate amyloid ␤ (A␤) formation from amyloid precursor protein (APP) in vitro. To determine whether loss of S1P sensitizes to A␤-mediated neurodegeneration, we investigated whether SK2 deficiency worsens pathology and memory in male J20 (PDGFB-APP SwInd) mice. SK2 deficiency greatly reduced A␤ content in J20 mice, associated with significant improvements in epileptiform activity and cross-frequency coupling measured by hippocampal electroencephalography. However, several key measures of APP SwInd-dependent neurodegeneration were enhanced on the SK2-null background, despite reduced A␤ burden. These included hippocampal volume loss, oligodendrocyte attrition and myelin loss, and impaired performance in Y-maze and social novelty memory tests. Inhibition of the endosomal cholesterol exporter NPC1 greatly reduced sphingosine phosphorylation in glial cells, linking loss of SK2 activity and S1P in AD to perturbed endosomal lipid metabolism. Our findings establish SK2 as an important endogenous regulator of both APP processing to A␤, and oligodendrocyte survival, in vivo. These results urge greater consideration of the roles played by oligodendrocyte dysfunction and altered membrane lipid metabolic flux as drivers of neurodegeneration in AD.

A Novel Function of Sphingosine Kinase 2 in the Metabolism of Sphinga-4,14-Diene Lipids

“…We have previously reported the loss of S1P and SphK2 activity early in the pathogenesis of Alzheimer's disease [23], and recently demonstrated that loss of SphK2 sensitizes to hippocampal atrophy and myelin loss in a mouse model of Alzheimer's disease [24]. We have also shown heightened anxiety in mice lacking SphK2 [25].…”

“…The brain is enriched with sphingolipids, so an increased proportion of d18:2 (4,14) sphingolipids may have important consequences for neuronal lipid domains and myelin integrity. We have reported that SphK2 deficiency synergizes with an amyloid-producing transgene to create severe myelin deficits [24]. It is possible that myelin structure and function is destabilized by an increased abundance of sphingadiene lipids in SphK2 −/− mice, and this should be investigated in future studies, potentially by crossing SphK2 −/− to FADS3 −/− mice.…”

“…In agreement with our data, Jojima et al [35] also found that both SphK1 and SphK2 catalyze sphingadiene phosphorylation as efficiently as sphingosine in vitro. Since SphK2 catalyzes the bulk of S1P synthesis in the brain [24,25,29], its absence shifts the equilibrium between sphingoid bases (sphingosine, sphingadiene) and their respective 1-phosphates in favor of the sphingoid bases. This is expected to result in more efficient re-acylation of these sphingoid bases to ceramides in the salvage pathway (Figure 1), producing the increase in ceramide levels observed in both brain and liver (Figure 3).…”

Transcriptomic and Network Analysis Identifies Shared and Unique Pathways across Dementia Spectrum Disorders

“…Interestingly, STAT3 has been shown to promote the activation of sphingosine kinases and the production of sphingosine 1 phosphate (S1P) in inflammation related pathways in cancer [35]. In the context of AD, the loss of sphingosine kinase 2 activity and SP1 production are key pathogenic drivers of Aβ-mediated neurodegeneration [36]. Another upregulated pathway of interest is PI3K-AKT signaling, which has been extensively implicated in the pathogenesis of AD given its crucial role mediating insulin effects in the brain and other functions in microglia and astrocytes [37].…”

Sphingolipids and Inositol Phosphates Regulate the Tau Protein Phosphorylation Status in Humanized Yeast

“…However, the discrepancies between different studies on changes in SL metabolism in AD are remarkable ( Crivelli et al, 2020 ). Intriguingly, studies on sphingosine-kinase and sphingosine-degrading enzymes have shown that lowering S1P decreases the Aβ production in vitro and in vivo ( Takasugi et al, 2011 ; Karaca et al, 2014 ; Lei et al, 2019 ). In addition, the relation between tau and the SL metabolism is poorly characterized, and there is no evidence of the implication of these lipids in its regulation.…”