Ceramide/Sphingosine 1-Phosphate Axis as a Key Target for Diagnosis and Treatment in Alzheimer's Disease and Other Neurodegenerative Diseases

Abstract

Alzheimer's disease (AD) is considered the most prevalent neurodegenerative disease and the leading cause of dementia worldwide. Sphingolipids, such as ceramide or sphingosine 1-phosphate, are bioactive molecules implicated in structural and signaling functions. Metabolic dysfunction in the highly conserved pathways to produce sphingolipids may lead to or be a consequence of an underlying disease. Recent studies on transcriptomics and sphingolipidomics have observed alterations in sphingolipid metabolism of both enzymes and metabolites involved in their synthesis in several neurodegenerative diseases, including AD. In this review, we highlight the most relevant findings related to ceramide and neurodegeneration, with a special focus on AD.

Keywords: Alzheimer’s disease; ceramide; metabolism; sphingolipidomics; sphingolipids; sphingosine 1-phosphate; tau; β-amyloid.

Figure 1

Sphingolipid metabolism. Single reactions are represented by solid arrows, while multiple-step reactions are shown as dashed arrows. Interrogation marks with dashed arrows point to possible mechanisms not yet described. Serine palmitoyltransferase (SPT), 3-keto-dihydrosphingosine reductase (KDR), ceramide Synthase (CerS) and dihydroceramide desaturase (DEGS), sphingomyelinase (SMase), acid sphingomyelinase (aSMase), sphingomyelin synthase (SMS), acid β-glucosidase (β-GCase), glucosylceramide synthase (GCS), ceramide synthase (CerS), sphingosine kinase (SphK), and sphingosine 1-phosphate phosphatase (SPP) are represented by their acronyms.

Figure 2

Involvement of Cer in Alzheimer’s disease. Several pieces of evidence support the involvement of Cer in the progression of AD, as it is interrelated with the formation of Aβ (A) and its neurotoxicity (B). Cer also plays a role in lipid peroxidation (C) and neuroinflammation (D) p75 neurotrophin receptor (P75NTR), β-secretase (BACE-1), amyloid precursor protein (APP), sphingomyelinase (SMase), β-amyloid (Aβ), ceramide (Cer), nitric oxide (NO), sphingosine 1-phosphate (S1P), pro-apoptotic protein Bcl-2-associated X protein (BAX), mitochondrial voltage-dependent anion channel 1 (VDAC-1), 4-Hydroxynonenal (HNE), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), inducible nitric oxide synthase (iNOS), glial fibrillary acidic protein (GFAP), tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β).