Sphingolipids in Alzheimer's disease, how can we target them?

Simone M Crivelli; Caterina Giovagnoni; Lars Visseren; Anna-Lena Scheithauer; Nienke de Wit; Sandra den Hoedt; Mario Losen; Monique T Mulder; Jochen Walter; Helga E de Vries; Erhard Bieberich; Pilar Martinez-Martinez

doi:10.1016/j.addr.2019.12.003

Sphingolipids in Alzheimer's disease, how can we target them?

Adv Drug Deliv Rev. 2020:159:214-231. doi: 10.1016/j.addr.2019.12.003. Epub 2020 Jan 3.

Affiliations

¹ Division of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands; Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA. Electronic address: s.crivelli@uky.edu.
² Division of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
³ Department of Neurology, University of Bonn, Bonn, Germany.
⁴ Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
⁵ Department of Internal Medicine, Division of Pharmacology, Vascular and Metabolic Diseases, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
⁶ Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
⁷ Department of Physiology, University of Kentucky College of Medicine, Lexington, KY, USA.
⁸ Division of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands. Electronic address: p.martinez@maastrichtuniversity.nl.

PMID: 31911096
DOI: 10.1016/j.addr.2019.12.003

Abstract

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.

Keywords: Alzheimer's disease; Blood brain barrier (BBB); Ceramide; Fingolimod (FTY720); GW4869; Sphingomyelin (SM); Sphingosine-1-phosphate (S1P); Tricyclic dibenzoazepines (TCA).

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Review

MeSH terms

Alzheimer Disease / metabolism*
Alzheimer Disease / therapy
Animals
Blood-Brain Barrier
Cell Death
Humans
Neurons / metabolism
Sphingolipids / metabolism*

Substances

Sphingolipids

Grants and funding

I01 BX003643/BX/BLRD VA/United States