Palmitate and ceramide induce human monocytic cell toxicity towards neuronal cells

Obesity is associated with increased risk of Alzheimer's disease (AD) but the mechanisms linking these conditions are poorly understood. Levels of saturated fatty acids and their metabolites (e.g., ceramides) are elevated in obesity and can induce inflammation in peripheral immune cells. Brain inflammation, which is mediated by activation of glial cells, is increased in AD. Our aim was to determine if elevated levels of saturated fatty acids or ceramides could induce inflammation and cause neurotoxin secretion from glial cells. Human THP‐1 monocytes and U‐ 373MG astrocytoma cell lines were used to model microglia and astroctyes, respectively. Incubation of THP‐1 cells, but not U‐ 373MG cells, with 125–250 μM palmitate for 48 h increased secretion of the pro‐inflammatory cytokines MCP‐1 and IL‐8 ( p <0.001). Transfer of conditioned media from palmitate‐treated THP‐1 cells to SH‐SY5Y neuroblastoma cells caused a significant increase in neuronal cell death ( p <0.001). Palmitate had no effect on U‐373 MG cell‐mediated neurotoxicity ( p >0.05). Similar to palmitate, treatment of THP‐1 cells with C2 ceramide significantly increased neurotoxicity ( p <0.001). These results indicate that increased circulating levels of palmitate or ceramides in obesity may contribute to neurodegeneration through inflammatory pathways involving microglia. Supported by the NSERC