The Role of Sphingolipids and Specialized Pro-Resolving Mediators in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is the leading cause of dementia worldwide giving rise to devastating forms of cognitive decline, which impacts patients' lives and that of their proxies. Pathologically, AD is characterized by extracellular amyloid deposition, neurofibrillary tangles and chronic neuroinflammation. To date, there is no cure that prevents progression of AD. In this review, we elaborate on how bioactive lipids, including sphingolipids (SL) and specialized pro-resolving lipid mediators (SPM), affect ongoing neuroinflammatory processes during AD and how we may exploit them for the development of new biomarker panels and/or therapies. In particular, we here describe how SPM and SL metabolism, ranging from ω-3/6 polyunsaturated fatty acids and their metabolites to ceramides and sphingosine-1-phosphate, initiates pro- and anti-inflammatory signaling cascades in the central nervous system (CNS) and what changes occur therein during AD pathology. Finally, we discuss novel therapeutic approaches to resolve chronic neuroinflammation in AD by modulating the SPM and SL pathways.

Keywords: Alzheimer’s disease; bioactive lipids; ceramide; neuroinflammation; specialized pro-resolving mediator; sphingolipids; sphingosine-1-phosphate.

Figure 1

Overview of the sphingolipid (SL) rheostat model and the interplay with specialized pro-resolving mediator (SPM) metabolism. Ceramide can be synthesized by ceramide synthases via the de novo and the salvage pathway from sphingosine or by hydrolysis of sphingomyelin by sphingomyelinase. Once generated, ceramide can act as substrate for other sphingolipids such as sphingosine and sphingosine-1-phosphate (S1P) via sphingosine kinase (SK). S1P can be catabolized into hexadecenal + phospho-ethanolamine by the action of sphingosine 1-phosphate lyase. Alternatively, SK can generate N-acetyl sphingosine via acetyl-CoA and sphingosine, followed by the acetylation of COX-2. In turn, this activates COX-2 mediated 15-HETE, 18-HEPE and 17-HDHA production, which can be converted to SPMs like such as 15R-LXA₄, RvE1, and RvD1, thereby providing a direct link between the SL and SPM pathways.

Figure 2

Chemical structure of Fingolimod together with three other more selective S1PR inhibitors; Siponimod, Ponesimod, and Ozanimod.

Figure 3

The role of sphingolipids and specialized pro-resolving mediators in health and disease. In healthy conditions, neurons maintain a proper balance of sphingolipids. The abundant SK1 enzyme deviates the sphingolipid pathway toward SPM production and secretion. Secreted SPMs reach perineuronal microglia, promoting their pro-resolving phenotype. Pro-resolving microglia maintain a healthy microenvironment by clearing amyloid beta through phagocytosis. In AD, there is a dysregulation of sphingolipids and SPMs, which correlates with the levels of hyperphosphorylated tau and Aβ. Reduced levels of the enzyme SK1 result in less SPM production and secretion. Microglia become pro-inflammatory, and start secreting pro-inflammatory cytokines. Aβ is no longer cleared, leading to the formation of extracellular amyloid plaques. These plaques further contribute to neurotoxicity.