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

Abstract

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.

Whole Body Vibration Therapy after Ischemia Reduces Brain Damage in Reproductively Senescent Female Rats

“…In models of brain ischemia, evidence for inflammasome activation has been reported with elevations in inflammatory proteins such as ASC, and caspase-1. Our previously published studies demonstrated elevations in inflammasome proteins in the hippocampus of aged rats [41,42]. Consistent with our findings, others have demonstrated increased pro-inflammatory cytokine levels in middle-aged female rats [43].…”

Activation and Regulation of Cellular Inflammasomes: Gaps in Our Knowledge for Central Nervous System Injury

“…For example, probenecid, an FDA-approved drug for the treatment of gout and hyperuricemia, inhibits inflammasome activation by high extracellular K þ in cultured neurons and astrocytes 18 and has been shown to decrease caspase-1 in the brain of aged rats. 76 Moreover, glyburide, typically used in the treatment of diabetes mellitus, inhibits NLRP3 inflammasome activation; 77 however, to date, glyburide has not been shown to inhibit inflammasome activation in the CNS. Other substances such as YVAD, PPADs, KN-62, and antibiotics ( Figure 3) have been suggested as possible therapeutics to block inflammasome activation, but these substances have not been successfully tested in the CNS.…”

Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation

“…[27][28][29][30][31] Neuronal Nlrp1 increased in rats submitted to spinal cord or sciatic nerve injury, 29,32 and in aging rat hippocampus or ethanol treated hippocampal slice cultures. 33,34 Aim2 induced pyroptosis in rat cortical neuron cultures and traumatic brain injury. 35 Nlrp1 has been reported in human brain pyramidal neurons 36 and inflammasome receptor mRNAs were observed in human neuron cultures and human Rasmussen's encephalitis.…”