Altered Composition of Ceramides and Sphingomyelin Distinctly Modulates the Organizational Landscape and Microdomain Dynamics of Neuronal Plasma Membrane: A Computational Microscopy of Alzheimer’s Brain

Alzheimer's disease (AD) is one of the leading causes of death in the elderly population. Currently, there is no available therapy that can stop the disease progression. Situations are much worse due to a lack of a clear understanding of disease pathogenesis and the unavailability of an appropriate biomarker for early diagnosis. Higher ceramide levels were strongly linked to an increased risk of AD. However, the effect of increased ceramide concentration on the spatiotemporal organization and dynamics of neuronal membranes in diseased conditions is poorly understood. Based on the lipidomics data, we have modeled biologically relevant neuronal model membranes for healthy brain (HB) and diseased condition AD brain (ADB). The effects of the increase in ceramides and the lowering of sphingomyelin on the overall membrane organization, fluidity, stability, and dynamics of membrane microdomains have been investigated through extensive molecular dynamics (MD) simulations. Healthy neuronal membranes are less curved than the ADB. In ADB, cholesterols exhibit a higher local enrichment around cholesterol, but its enrichment decreases significantly around ceramide. In contrast, ceramides are enriched around themselves in the ADB. Enhancement in the ceramide content promotes cholesterol-sphingomyelin-enriched but ceramide-deficient microdomains. At the same time, ceramides tend to coalesce and form ceramide-enriched microdomains with a significantly longer residence time. The AD neuronal membrane has a higher number of highly stable ceramide-exclusive microdomains. Ceramide-enriched microdomains are known to enhance amyloidogenic processing. The study provides insight into the role of ceramides and sphingomyelins in AD disease pathogenesis and enhances the potential of lipid-based biomarkers for early detection.