Role of the Alzheimer's Disease Enzymes and Proteins in Sphingolipid and Glycosphingolipid Homeostasis

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We recently showed the link between sphingomyelinase and the Amyloid precursor protein (APP). Beside its detrimental role in Alzheimer´s disease, this showed for the first time that APP also has a physiological function. Our recent data suggest that the APP function is not limited to sphingomyelinases, but that other sphingolipid enzymes are regulated by APP as well. For the GD3-synthase (GD3S) we could elucidate the mechanism how this enzyme is regulated by APP. Whereas Amyloid-β (Aβ) directly regulates enzyme activity by modulating substrate availability, the APP intracellular domain (AICD) regulates the expression level of the enzyme. Beside the GD3S at least 3 more sphingolipid enzymes were identified, which suggest a common mechanism. Focus of this project is to investigate the mechanism how the other enzymes are regulated by APP, and to elucidate the potential general mechanism of Aβ and AICD dependent regulation in sphingolipid homeostasis. As sphingolipids play an abundant role in synaptic processes, APP dependent alterations will directly affect synaptic function - another goal of this proposal. Studies will be done with cell culture, cell free assays and knock out animals to validate in vivo relevance. Expected is a better understanding the role of APP in sphingolipid homeostasis, possibly leading to new therapeutic approaches.