Sphingolipid Signaling and Metabolism in Neuronal and Glial Cells: Implications for Cerebrovascular and Neurodegenerative Disorders

Sphingolipids are essential bioactive lipids that play pivotal roles in maintaining the structural integrity of cellular membranes and regulating key signaling pathways in the central nervous system (CNS). In both neuronal and glial cells, sphingolipid metabolism regulates diverse processes, including cell survival, apoptosis, neuroinflammation, and myelination. Increasing evidence implicates dysregulation of sphingolipid pathways in the pathogenesis of various CNS disorders, notably cerebrovascular diseases such as small vessel disease and stroke, as well as neurodegenerative conditions including Alzheimer's disease, cerebral amyloid angiopathy, Parkinson's disease, and multiple sclerosis. This review summarizes the current advances in sphingolipid metabolism and signaling in the brain, with a focus on the functional interplay between neurons and glia, as well as the mechanisms by which disrupted sphingolipid homeostasis contributes to CNS pathology. Key sphingolipid metabolites such as ceramide, ceramide-1-phosphate, and sphingosine-1-phosphate emerge as critical mediators of neuroinflammation, blood-brain barrier disruption, and cognitive impairment. Furthermore, we explore emerging therapeutic strategies targeting sphingolipid pathways and their potential to slow disease progression and improve neurological outcomes. A deeper understanding of the roles of neuronal and glial sphingolipids in brain health and disease may advance the development of novel diagnostic tools and therapeutic strategies for cerebrovascular and neurodegenerative disorders.