Journal
NEUROBIOLOGY OF AGING
Volume 34, Issue 12, Pages 2715-2725Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2013.05.018
Keywords
Alzheimer's disease; Amyloid beta protein; Cathepsin B; Chromogranin A; Interleukin-1 beta; Microglia; Nuclear factor-kappa B; Toll-like receptor 4
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Funding
- JST, CREST
- Grants-in-Aid for Scientific Research [24659827, 24791979] Funding Source: KAKEN
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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.
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