Reduced sphingosine kinase-1 and enhanced sphingosine 1-phosphate lyase expression demonstrate deregulated sphingosine 1-phosphate signaling in Alzheimer's disease.
BACKGROUND
The accumulation of beta amyloid (Aβ) peptides, a hallmark of Alzheimer's disease (AD) is related to mechanisms leading to neurodegeneration. Among its pleiotropic cellular effects, Aβ accumulation has been associated with a deregulation of sphingolipid metabolism. Sphingosine 1-phosphate (S1P) derived from sphingosine is emerging as a critical lipid mediator regulating various biological activities including cell proliferation, survival, migration, inflammation, or angiogenesis. S1P tissue level is low and kept under control through equilibrium between its synthesis mostly governed by sphingosine kinase-1 (SphK1) and its degradation by sphingosine 1-phosphate lyase (SPL). We have previously reported that Aβ peptides were able to decrease the activity of SphK1 in cell culture models, an effect that could be blocked by the prosurvival IGF-1/IGF-1R signaling.


RESULTS
Herein, we report for the first time the expression of both SphK1 and SPL by immunohistochemistry in frontal and entorhinal cortices from 56 human AD brains. Immunohistochemical analysis revealed a decreased expression of SphK1 and an increased expression of SPL both correlated to amyloid deposits in the entorhinal cortex. Otherwise, analysis of brain tissue extracts showed a decrease of SphK1 expression in AD brains whereas SPL expression was increased. The content of IGF-1R, an activator of SphK1, was found decreased in AD brains as well as S1P1, the major receptor for S1P.


CONCLUSIONS
Collectively, these results highlight the importance of S1P in AD suggesting the existence of a global deregulation of S1P signaling in this disease from its synthesis by SphK1 and degradation by SPL to its signaling by the S1P1 receptor.
Johnatan
J
Ceccom
Najat
N
Loukh
Valérie
V
Lauwers-Cances
Christian
C
Touriol
Yvan
Y
Nicaise
Catherine
C
Gentil
Emmanuelle
E
Uro-Coste
Stuart
S
Pitson
Claude Alain
CA
Maurage
Charles
C
Duyckaerts
Olivier
O
Cuvillier
CHU Toulouse, Service d'Anatomie Pathologique, 31059 Toulouse, France. delisle.b@chu-toulouse.fr.
Marie-Bernadette
MB
Delisle
D000368:Aged; D000369:Aged, 80 and over; D000446:Aldehyde-Lyases / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013223:Statistics as Topic; D000099157:Sphingosine Kinase
D000446:Aldehyde-Lyases; D016229:Amyloid beta-Peptides; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase; C022649:sphingosine 1-phosphate lyase (aldolase)