title: Heightened inflammasome activation is linked to age-related cognitive impairment in Fischer 344 rats.
abstract: BACKGROUND
  Members 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  Our 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.
authors: Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
authors: Lana J
authors: LJ
authors: Mawhinney
authors: Juan Pablo
authors: JP
authors: de Rivero Vaccari
authors: Gordon A
authors: GA
authors: Dale
authors: Robert W
authors: RW
authors: Keane
authors: Helen M
authors: HM
authors: Bramlett
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology / Q000523:psychology; D000818:Animals; D003072:Cognition Disorders / Q000473:pathology*; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D058847:Inflammasomes / Q000378:metabolism* / Q000502:physiology; D008297:Male; D008569:Memory Disorders / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344; D015854:Up-Regulation / Q000502:physiology
chemical_list: D016207:Cytokines; D058847:Inflammasomes; D009419:Nerve Tissue Proteins; C526260:Nlrp1a protein, rat