TY - JOUR
T1 - Sphingosine Kinase 2 Potentiates Amyloid Deposition but Protects against Hippocampal Volume Loss and Demyelination in a Mouse Model of Alzheimer's Disease
AU - Lei, Mona
AU - Teo, Jonathan D.
AU - Song, Huitong
AU - McEwen, Holly P.
AU - Yup Lee, Jun
AU - Couttas, Timothy A.
AU - Duncan, Thomas
AU - Chesworth, Rose
AU - Bertz, Josefine
AU - Przybyla, Magdalena
AU - Van Eersel, Janet
AU - Heng, Benjamin
AU - Guillemin, Gilles J.
AU - Ittner, Lars M.
AU - Fath, Thomas
AU - Garner, Brett
AU - Ittner, Arne
AU - Karl, Tim
AU - Don, Anthony S.
PY - 2019/11/27
Y1 - 2019/11/27
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - myelin
KW - neuroprotection
KW - oligodendrocyte
KW - sphingosine 1-phosphate
KW - sphingosine kinase
UR - http://www.scopus.com/inward/record.url?scp=85075814651&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/NHMRC/1100626
UR - http://purl.org/au-research/grants/NHMRC/1102012
UR - http://purl.org/au-research/grants/NHMRC/1141789
UR - http://purl.org/au-research/grants/NHMRC/1081916
UR - http://purl.org/au-research/grants/NHMRC/1143978
UR - http://purl.org/au-research/grants/NHMRC/1132524
UR - http://purl.org/au-research/grants/NHMRC/1136241
UR - http://purl.org/au-research/grants/NHMRC/1110400
UR - http://purl.org/au-research/grants/NHMRC/1095215
UR - http://purl.org/au-research/grants/ARC/DP170100781
UR - http://purl.org/au-research/grants/ARC/DP170100843
U2 - 10.1523/JNEUROSCI.0524-19.2019
DO - 10.1523/JNEUROSCI.0524-19.2019
M3 - Article
C2 - 31641049
AN - SCOPUS:85075814651
VL - 39
SP - 9645
EP - 9659
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 48
ER -