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

Mona Lei, Jonathan D. Teo, Huitong Song, Holly P. McEwen, Jun Yup Lee, Timothy A. Couttas, Thomas Duncan, Rose Chesworth, Josefine Bertz, Magdalena Przybyla, Janet Van Eersel, Benjamin Heng, Gilles J. Guillemin, Lars M. Ittner, Thomas Fath, Brett Garner, Arne Ittner, Tim Karl, Anthony S. Don

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

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 β (Aβ) formation from amyloid precursor protein (APP) in vitro. To determine whether loss of S1P sensitizes to Aβ-mediated neurodegeneration, we investigated whether SK2 deficiency worsens pathology and memory in male J20 (PDGFB-APP SwInd ) mice. SK2 deficiency greatly reduced Aβ 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 Aβ 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 Aβ, and oligodendrocyte survival, invivo. These results urge greater consideration of the roles played by oligodendrocyte dysfunction and altered membrane lipid metabolic flux as drivers of neurodegeneration in AD.

Original languageEnglish
Pages (from-to)9645-9659
Number of pages15
JournalThe Journal of neuroscience : the official journal of the Society for Neuroscience
Volume39
Issue number48
DOIs
Publication statusPublished - 27 Nov 2019
Externally publishedYes

Keywords

  • Alzheimer's disease
  • myelin
  • neuroprotection
  • oligodendrocyte
  • sphingosine 1-phosphate
  • sphingosine kinase

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