Novelty of Sphingolipids in the Central Nervous System Physiology and Disease: Focusing on the Sphingolipid Hypothesis of Neuroinflammation and Neurodegeneration

Abstract

For decades, lipids were confined to the field of structural biology and energetics as they were considered only structural constituents of cellular membranes and efficient sources of energy production. However, with advances in our understanding in lipidomics and improvements in the technological approaches, astounding discoveries have been made in exploring the role of lipids as signaling molecules, termed bioactive lipids. Among these bioactive lipids, sphingolipids have emerged as distinctive mediators of various cellular processes, ranging from cell growth and proliferation to cellular apoptosis, executing immune responses to regulating inflammation. Recent studies have made it clear that sphingolipids, their metabolic intermediates (ceramide, sphingosine-1-phosphate, and N-acetyl sphingosine), and enzyme systems (cyclooxygenases, sphingosine kinases, and sphingomyelinase) harbor diverse yet interconnected signaling pathways in the central nervous system (CNS), orchestrate CNS physiological processes, and participate in a plethora of neuroinflammatory and neurodegenerative disorders. Considering the unequivocal importance of sphingolipids in CNS, we review the recent discoveries detailing the major enzymes involved in sphingolipid metabolism (particularly sphingosine kinase 1), novel metabolic intermediates (N-acetyl sphingosine), and their complex interactions in CNS physiology, disruption of their functionality in neurodegenerative disorders, and therapeutic strategies targeting sphingolipids for improved drug approaches.

Involvement of Ceramide Metabolism in Cerebral Ischemia

“…In recent years, electrospray ionization mass spectrometry approaches to measuring sphingolipids (sphingolipidomics) in plasma have revealed their possible use as vascular risk biomarkers in diabetes and cardiovascular diseases ( Gaggini et al, 2021 ; Tippetts et al, 2021 ). Moreover, sphingolipidomics also showed its ability to study sphingolipids as potential biomarkers associated with neurodegenerative processes ( Ayub et al, 2021 ), demonstrating the involvement of sphingolipids in their underlying molecular mechanisms. Specifically, recent works on cerebral ischemia showed an alteration of the sphingolipid profile, both in pre-clinical ( Chao et al, 2019 ) and clinical studies ( Sun et al, 2017 ; Gui et al, 2020 ; Lee et al, 2021 ).…”

Ceramide and Sphingosine-1-Phosphate in Neurodegenerative Disorders and Their Potential Involvement in Therapy

“…Recently, a novel sphinolipid, the N-acetyl sphingosine (N-AS), which is an intermediate product in Sph metabolism, has been reported to have a role in the central nervous system physiology and disease [ 117 ]. It has been shown that acetyl-CoA binds to the ATP-binding domain in SphK1 and transfers the acetyl group to Sph, leading to the production of N-AS.…”

“…In microglia N-AS levels are reduced due to the reduced availability of acetyl-CoA in these cells. It has also been demonstrated that the decrease in N-AS synthesis by acetyl-CoA deficient microglia is associated to a lower acetylation of COX2 which affect the release of specialized pro-resolving lipid mediators causing poor resolution of neuroinflammation and AD pathology [ 117 ].…”

Plasma Ceramides Pathophysiology, Measurements, Challenges, and Opportunities

“…For their importance in key cellular pathways, ceramides and their precursor or downstream metabolites have been involved in several pathophysiological conditions such as cancer, neurodegeneration, and cardiometabolic diseases [4,5,[42][43][44][45]. In particular, circulating ceramides are elevated in obese subjects, prediabetes, and type 2 diabetes, and correlated with the risk of developing atherosclerosis and cardiovascular disease [46].…”

“…Circulating ceramides may also predict cardiovascular disease (CVD) (e.g., coronary artery disease-levels of CAD, stroke, heart failure, and atrial fibrillation) [3]. Recent studies have later expanded the role of ceramides to other conditions, such as neurodegenerative diseases and cancer [4][5][6]. Interestingly, in the complex relationship between ceramides, T2D and CVD, exercise, and cognitive functions, recent data demonstrated that specific ceramide species associated with T2D in patients with CAD predicted poorer cognitive responses (e.g., less improvement in verbal memory, and less visuospatial memory improvement) to exercise [7].…”