Heightened inflammasome activation is linked to age-related cognitive impairment in Fischer 344 rats

BMC Neuroscience

Research Article

Lana J Mawhinney¹  Juan Pablo de Rivero Vaccari¹  Helen M Bramlett²  Gordon A Dale³  Robert W Keane⁴ 

[1] Department of Neurological Surgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, 33136, Miami, FL, USA;The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, 33136, Miami, FL, USA;Department of Neurological Surgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, 33136, Miami, FL, USA;The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, 33136, Miami, FL, USA;Bruce W. Carter Department of Veterans Affairs Medical Center, 1201 N.W. 16th Street, 33125, Miami, FL, USA;Department of Physiology and Biophysics, University of Miami Miller School of Medicine, 1600 NW 10th Avenue, 33136, Miami, Florida, USA;The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, 33136, Miami, FL, USA;Department of Physiology and Biophysics, University of Miami Miller School of Medicine, 1600 NW 10th Avenue, 33136, Miami, Florida, USA;

关键词: P2X7 Receptor;    Spatial Learning;    Morris Water Maze;    Probenecid;    NLRP1 Inflammasome;   

DOI  :  10.1186/1471-2202-12-123

 received in 2011-08-25, accepted in 2011-12-01,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundMembers of the mammalian nucleotide binding domain, leucine-rich repeat (LRR)-containing receptor (NLR) family of proteins are key modulators of innate immunity regulating inflammation. Our previous work has shown that among the members of this family, NLRP1/NALP1, present in neurons, plays a crucial role in inflammasome formation and the production of the inflammatory cytokines interleukin (IL) -1β and IL-18 after various types of central nervous system injury.ResultsWe investigated whether age-related cognitive decline may involve a heightened inflammatory response associated with activation of the NLRP1 inflammasome in the hippocampus. Young (3 months) and aged (18 months) male Fischer 344 rats were tested in a spatial acquisition task via Morris water maze. Following behavioral testing, hippocampal lysates were assayed for expression of NLRP1 inflammasome components and inflammatory cytokines. Hippocampal lysates from aged rats showed significantly higher levels of NLRP1 inflammasome constituents, caspase-1, caspase-11, the purinergic receptor P2X7, pannexin-1 and X-linked inhibitor of apoptosis (XIAP) than lysates from younger animals. Following treatment with probenecid, an inhibitor or pannexin-1, aged animals demonstrated reduction in inflammasome activation and improvement in spatial learning performance.ConclusionsOur behavioral findings are consistent with increases in IL-1β and IL-18 that have been previously shown to correlate with spatial learning deficits. Probenecid reduced activated caspase-1 and ameliorated spatial learning deficits in aged rats. Thus, aging processes stimulate activation of the NLRP1 inflammasome and secretion of IL-1β and IL-18 that may contribute to age-related cognitive decline in the growing elderly population. Moreover, probenecid may be potentially useful as a therapy to improve cognitive outcomes in the aging population.

【 授权许可】

Unknown   
© Mawhinney et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.