Schematic representation of the sphingolipid rheostat in AD context. Ceramide can be generated de novo or by hydrolysis of sphingomyelin by sphingomyelinase. Ceramide is subsequently metabolized by ceramidase to generate sphingosine which in turn produces sphingosine 1-phosphate through phosphorylation by sphingosine kinase-1 and sphingosine kinase-2. All these reactions are reversible. Sphingosine 1-phosphate can be catabolized into hexadecenal + phospho-ethanolamine by the action of sphingosine 1-phosphate lyase. Sphingosine 1-phosphate exerts intracellular signaling which can promote, calcium mobilization, epigenetic modulation and survival effects. S1P has also extracellular effects by signaling through 5 G protein-coupled receptors. The agonist FTY720 can bind S1P1,3,4,5. IGF-1/IGF-1R signaling pathway is able to activate SphK1, inducing its translocation to the plasma membrane. In AD, Aβ peptide is able to upregulate sphingomyelinase activity which consequently increases the level of ceramide. In turn, ceramide stabilizes BACE-1 which increases APP cleavage leading to generation of Aβ peptide . S1P level as IGF-1R level are decreased in AD . SMSyn, sphingomyelin synthase; SMase, sphingomyelinase; Cerase, ceramidase; CerSyn, ceramide synthase; Sph, sphingosine; SphK1/2, sphingosine kinase 1/2; S1Pase, sphingosine 1-phosphate phosphatase.