Sphingosine-1-phosphate and Alzheimer's disease

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Sphingosine-1-phosphate (S1P) regulates a wide range of cellular processes including proliferation, differentiation, motility, cytoskeleton rearrangements and calcium homeostasis. Although S1P promotes cell survival in peripheral tissues, increased S1P levels appear to be toxic in terminally differentiated primary neurons. Intriguingly, S1P dependent neurotoxicity shows similarity to that of the amyloid ß-peptide (Aß), which constitutes amyloid plaques, characteristic for Alzheimer’s disease (AD). Both S1P and Aß induce an aberrant reactivation of cell cycle events. Preliminary experiments demonstrate a functional relation of S1P and the ß-amyloid precursor protein (APP). The accumulation of S1P in S1P-lyase deficient cells induces increased expression of APP and affects its proteolytic processing. The central aim of this project is to identify and characterize molecular mechanisms that underlie the S1P dependent metabolism of APP and neuronal death.