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*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

25 Citations (Web of Science)

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. (C) 2020 Elsevier B.V. All rights reserved.

Original languageEnglish
Pages (from-to)214-231
Number of pages18
JournalAdvanced Drug Delivery Reviews
Volume159
DOIs
Publication statusPublished - 2020

Keywords

  • Ceramide
  • Sphingosine-1-phosphate (S1P)
  • Sphingomyelin (SM)
  • Alzheimer's disease
  • Blood brain barrier (BBB)
  • GW4869
  • Tricyclic dibenzoazepines (TCA)
  • Fingolimod (FTY720)
  • AMYLOID PRECURSOR PROTEIN
  • NERVE GROWTH-FACTOR
  • KINASE-C-ZETA
  • BLOOD-BRAIN-BARRIER
  • CERAMIDE SYNTHASE 2
  • SERINE PALMITOYLTRANSFERASE INHIBITOR
  • MITOCHONDRIAL OUTER-MEMBRANE
  • CULTURED HIPPOCAMPAL-NEURONS
  • P75 NEUROTROPHIN RECEPTOR
  • ANTIGEN-BINDING PROTEIN

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