Ceramide: a central regulator in Alzheimer's disease pathogenesis

Ceramide is a key component of sphingolipid metabolism and functions as a lipid second messenger. Sphingolipids are crucial for maintaining the nervous system, particularly in differentiation and development. Ceramide supports hippocampal growth but, at elevated levels, can impair dendritic cell function. During aging and neurodegenerative diseases like Alzheimer's disease (AD), intracellular ceramide production and accumulation increase, negatively impacting cognitive functions. High ceramide levels are linked to the progression of AD pathology, significantly contributing to amyloid β (Aβ) accumulation, tau tangle formation, insulin resistance, oxidative stress, and neuroinflammation. Ceramide facilitates the production and aggregation of Aβ peptides, leading to neurotoxic plaque formation. Its dysregulation is associated with abnormal tau protein phosphorylation, resulting in neurofibrillary tangles (NFTs). In addition, elevated ceramide levels can trigger brain inflammation by promoting the release of pro-inflammatory cytokines and activating microglia. This accumulation also enhances oxidative stress in neurons, damaging cellular components such as proteins, lipids, and DNA. This review will help in deeper understanding of the molecular pathways altered via ceramide metabolism and accumulation involved in the AD pathology. The cellular and pathological mechanisms of ceramide and their impact on Alzheimer's disease pathophysiology. A deeper understanding of ceramide-mediated effects in aging and AD could pave the way for innovative therapeutic strategies targeting ceramide metabolism to treat neurodegenerative diseases and age-related cognitive decline.