Altered levels of sphingolipids and their metabolites in the brain, and the related downstream effects on neuronal homeostasis and the immune system, provide a framework for understanding mechanisms in neurodegenerative disorders and for developing new intervention strategies. In this review we will discuss: the metabolites of sphingolipids that function as second messengers; and functional aberrations of the pathway resulting in Alzheimer's disease (AD) pathophysiology. Focusing on the central product of the sphingolipid pathway ceramide, we describ approaches to pharmacologically decrease ceramide levels in the brain and we argue on how the sphingolipid pathway may represent a new framework for developing novel intervention strategies in AD. We also highlight the possible use of clinical and non-clinical drugs to modulate the sphingolipid pathway and sphingolipid-related biological cascades.

Additional Metadata
Keywords Alzheimer's disease, Blood brain barrier (BBB), Ceramide, Fingolimod (FTY720), GW4869, Sphingomyelin (SM), Sphingosine-1-phosphate (S1P), Tricyclic dibenzoazepines (TCA)
Persistent URL dx.doi.org/10.1016/j.addr.2019.12.003, hdl.handle.net/1765/124161
Journal Advanced Drug Delivery Reviews
Citation
Crivelli, S.M. (Simone M.), Giovagnoni, C. (Caterina), Visseren, L. (Lars), Scheithauer, A.-L. (Anna-Lena), de Wit, N. (Nienke), den Hoedt, S. (Sandra), … Martínez-Martínez, P. (2020). Sphingolipids in Alzheimer's disease, how can we target them?. Advanced Drug Delivery Reviews. doi:10.1016/j.addr.2019.12.003