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.
|Number of pages||18|
|Journal||Advanced Drug Delivery Reviews|
|State||Published - Jan 2020|
Bibliographical noteFunding Information:
This work was supported by grants to SMC, NMdW, SdH, MTM, JW, AR, PMM, and HEV from ZonMw Memorabel program (projectnr: 733050105 ). PMM is also supported by the International Foundation for Alzheimer Research (ISAO) (projectnr: 14545 ). EB is supported by R01AG034389 , R01NS095215 , VA grant I01 BX003643 and NSF 1615874 . SMC received a travel grant support from Alzheimer Netherlands to visit the laboratory of EB, University of Kentucky , Lexington KY, USA.
© 2020 Elsevier B.V.
- Alzheimer's disease
- Blood brain barrier (BBB)
- Fingolimod (FTY720)
- Sphingomyelin (SM)
- Sphingosine-1-phosphate (S1P)
- Tricyclic dibenzoazepines (TCA)
ASJC Scopus subject areas
- Pharmaceutical Science