Differential pathways for interleukin-1β production activated by chromogranin A and amyloid β in microglia

Although chromogranin A (CGA) is frequently present in Alzheimer's disease (AD), senile plaques associated with microglial activation, little is known about basic difference between CGA and fibrillar amyloid-beta (fA beta) as neuroinflammatory factors. Here we have compared the interleukin-1 beta (IL-1 beta) production pathways by CGA and fA beta in microglia. In cultured microglia, production of IL-1 beta was induced by CGA, but not by fA beta. CGA activated both nuclear factor-kappa B (NF-kappa B) and proecaspase-1, whereas fA beta activated proecaspase-1 only. For the activation of proecaspase-1, both CGA and fA beta needed the enzymatic activity of cathepsin B (CatB), but only fA beta required cytosolic leakage of CatB and the NLRP3 inflammasome activation. In contrast, fA beta induced the IL-1 beta secretion from microglia isolated from the aged mouse brain. In AD brain, highly activated microglia, which showed intense immunoreactivity for CatB and IL-1 beta, surrounded CGA-positive plaques more frequently than A beta-positive plaques. These observations indicate differential pathways for the microglial IL-1 beta production by CGA and fA beta, which may aid in better understanding of the pathological significance of neuroinflammation in AD. (C) 2013 Elsevier Inc. All rights reserved.