P2‐116: Activation of NLC4 inflammasome in primary rat astrocytes by palmitate enhances Alzheimer's disease–like changes in primary neurons

Abstract

Alzheimer's disease is a devastating neurodegenerative disease and characterized by accumulation of A b, but the mechanisms leading to neuronal dysfunction has not been fully elucidated. Many studies suggest that inflammatory and immunological processes from astroyctes and microglia are central to the initiation and progression of Alzheimer's disease, with interleukin 1 b (IL-1 b) as a key cytokine in the inflammatory response. IL-1 b maturation involves activation of a protein complex, inflammasome. Activation of different receptors of inflammasome is cell specific, and dependent upon the type of stimulation. Our studies show that saturated free-fatty acid, palmitate (PA) increase IL-1 b secretion by astrocytes, which in turn, upregulates A b level in primary rat neurons. However, the molecular mechanism by which PA induces IL-1 b secretion by the astrocytes is unknown. Western blot, Quantitative real time polymerase chain reaction, enzyme-linked immunosorbent assay, immunocytochemistry and RNA interference were performed. Inflammasome includes caspase1, apoptosis-associated speck-like protein containing a CARD (ASC) and cytoplasmic receptors of NLR family. Our data demonstrate that PA induces IL-1 b production from primary rat astrocytes. The active form of caspase1 involved in the maturation of IL-1 b is upregulated upon PA treatment, and silencing caspase1 decreases IL-1 b level. ASC is also increased significantly and silencing ASC downregulates the IL-1 b level. This indicates that components of the inflammasome are involved in the maturation of IL-1 b in primary astrocytes. Further studies confirm that cytoplasmic receptors, namely NOD-like receptor family CARD doman containing 4 (NLRC4), is required for activation of the inflammasome and the release of IL-1 b by primary rat astrocytes upon PA treatment. Our findings indicate that the activation of the NLRC4 inflammasome in primary rat astrocytes by PA may play a critical role in the inflammatory response in Alzheimer's disease.