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Research Articles, Neurobiology of Disease

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 and Anthony S. Don
Journal of Neuroscience 27 November 2019, 39 (48) 9645-9659; DOI: https://doi.org/10.1523/JNEUROSCI.0524-19.2019
Mona Lei
1Centenary Institute, University of Sydney, Camperdown 2006, New South Wales, Australia,
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Jonathan D. Teo
1Centenary Institute, University of Sydney, Camperdown 2006, New South Wales, Australia,
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Huitong Song
1Centenary Institute, University of Sydney, Camperdown 2006, New South Wales, Australia,
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Holly P. McEwen
1Centenary Institute, University of Sydney, Camperdown 2006, New South Wales, Australia,
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Jun Yup Lee
1Centenary Institute, University of Sydney, Camperdown 2006, New South Wales, Australia,
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Timothy A. Couttas
1Centenary Institute, University of Sydney, Camperdown 2006, New South Wales, Australia,
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Thomas Duncan
2Brain and Mind Centre, Sydney Medical School, University of Sydney, Camperdown 2006, New South Wales, Australia,
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Rose Chesworth
3School of Medicine, Western Sydney University, Campbelltown 2560, New South Wales, Australia,
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Josefine Bertz
4Dementia Research Centre, Faculty of Health and Medical Sciences,
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Magdalena Przybyla
4Dementia Research Centre, Faculty of Health and Medical Sciences,
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Janet Van Eersel
4Dementia Research Centre, Faculty of Health and Medical Sciences,
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Benjamin Heng
5MND Research Centre, Neuroinflammation Group, Macquarie University, Sydney 2109, New South Wales, Australia,
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Gilles J. Guillemin
5MND Research Centre, Neuroinflammation Group, Macquarie University, Sydney 2109, New South Wales, Australia,
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Lars M. Ittner
4Dementia Research Centre, Faculty of Health and Medical Sciences,
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Thomas Fath
4Dementia Research Centre, Faculty of Health and Medical Sciences,
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Brett Garner
6Illawarra Health and Medical Research Institute, 7School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong 2522, New South Wales, Australia,
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Arne Ittner
4Dementia Research Centre, Faculty of Health and Medical Sciences,
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Tim Karl
3School of Medicine, Western Sydney University, Campbelltown 2560, New South Wales, Australia, 8Neuroscience Research Australia, Randwick 2031, New South Wales, Australia, and
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Anthony S. Don
1Centenary Institute, University of Sydney, Camperdown 2006, New South Wales, Australia, 9NHMRC Clinical Trials Centre, University of Sydney, Camperdown 2006, New South Wales, Australia
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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-APPSwInd) 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 APPSwInd-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, 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 Aβ 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 Aβ 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 Aβ-mediated neurodegeneration by attenuating oligodendrocyte survival and promoting hippocampal atrophy, despite reduced Aβ burden. Our findings support a model in which Aβ-independent sensitizing influences such as loss of neuroprotective S1P are more important drivers of neurodegeneration than gross Aβ concentration or plaque density.

  • Alzheimer's disease
  • myelin
  • neuroprotection
  • oligodendrocyte
  • sphingosine 1-phosphate
  • sphingosine kinase
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The Journal of Neuroscience: 39 (48)
Journal of Neuroscience
Vol. 39, Issue 48
27 Nov 2019
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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
Journal of Neuroscience 27 November 2019, 39 (48) 9645-9659; DOI: 10.1523/JNEUROSCI.0524-19.2019

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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
Journal of Neuroscience 27 November 2019, 39 (48) 9645-9659; DOI: 10.1523/JNEUROSCI.0524-19.2019
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Keywords

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

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