| First Author | Lei M | Year | 2019 |
| Journal | J Neurosci | Volume | 39 |
| Issue | 48 | Pages | 9645-9659 |
| PubMed ID | 31641049 | Mgi Jnum | J:282353 |
| Mgi Id | MGI:6380600 | Doi | 10.1523/JNEUROSCI.0524-19.2019 |
| Citation | Lei M, et al. (2019) Sphingosine Kinase 2 Potentiates Amyloid Deposition but Protects against Hippocampal Volume Loss and Demyelination in a Mouse Model of Alzheimer's Disease. J Neurosci 39(48):9645-9659 |
| abstractText | 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 beta (Abeta) formation from amyloid precursor protein (APP) in vitro To determine whether loss of S1P sensitizes to Abeta-mediated neurodegeneration, we investigated whether SK2 deficiency worsens pathology and memory in male J20 (PDGFB-APPSwInd) mice. SK2 deficiency greatly reduced Abeta content in J20 mice, associated with significant improvements in epileptiform activity and cross-frequency coupling measured by hippocampal electroencephalography. However, several key measures of APPSwInd-dependent neurodegeneration were enhanced on the SK2-null background, despite reduced Abeta 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 Abeta, 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.SIGNIFICANCE STATEMENT Genetic, neuropathological, and functional studies implicate both Abeta and altered lipid metabolism and/or signaling as key pathogenic drivers of Alzheimer's disease. In this study, we first demonstrate that the enzyme SK2, which generates the signaling lipid S1P, is required for Abeta formation from APP in vivo Second, we establish a new role for SK2 in the protection of oligodendrocytes and myelin. Loss of SK2 sensitizes to Abeta-mediated neurodegeneration by attenuating oligodendrocyte survival and promoting hippocampal atrophy, despite reduced Abeta burden. Our findings support a model in which Abeta-independent sensitizing influences such as loss of neuroprotective S1P are more important drivers of neurodegeneration than gross Abeta concentration or plaque density. |
