期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：36
页码：E5078-E5087
DOI：10.1073/pnas.1514486112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThere is a growing understanding that inflammation impairs synaptic plasticity and cognition and that the aged brain has an elevated sensitivity to cognitive impairment by the proinflammatory cytokine interleukin 1{beta} (IL-1{beta}). IL-1{beta} activates different pathways via AcP (proinflammatory) or AcPb (prosurvival) IL-1 receptor subunits. This study demonstrates that the IL-1 receptor subunit system undergoes an age-dependent reconfiguration in hippocampal synapses. This previously undescribed reconfiguration, characterized by an increase in the AcP/AcPb ratio, is responsible for potentiating impairments of synaptic plasticity and memory by IL-1{beta}. Our data reveal a previously unidentified mechanism that explains the age-related vulnerability of hippocampal function to impairment by inflammation and adds another dimension beyond glia to understanding how inflammation causes cognitive decline in aging. In the aged brain, synaptic plasticity and memory show increased vulnerability to impairment by the inflammatory cytokine interleukin 1{beta} (IL-1{beta}). In this study, we evaluated the possibility that synapses may directly undergo maladaptive changes with age that augment sensitivity to IL-1{beta} impairment. In hippocampal neuronal cultures, IL-1{beta} increased the expression of the IL-1 receptor type 1 and the accessory coreceptor AcP (proinflammatory), but not of the AcPb (prosurvival) subunit, a reconfiguration that potentiates the responsiveness of neurons to IL-1{beta}. To evaluate whether synapses develop a similar heightened sensitivity to IL-1{beta} with age, we used an assay to track long-term potentiation (LTP) in synaptosomes. We found that IL-1{beta} impairs LTP directly at the synapse and that sensitivity to IL-1{beta} is augmented in aged hippocampal synapses. The increased synaptic sensitivity to IL-1{beta} was due to IL-1 receptor subunit reconfiguration, characterized by a shift in the AcP/AcPb ratio, paralleling our culture data. We suggest that the age-related increase in brain IL-1{beta} levels drives a shift in IL-1 receptor configuration, thus heightening the sensitivity to IL-1{beta}. Accordingly, selective blocking of AcP-dependent signaling with Toll-IL-1 receptor domain peptidomimetics prevented IL-1{beta}-mediated LTP suppression and blocked the memory impairment induced in aged mice by peripheral immune challenge (bacterial lipopolysaccharide). Overall, this study demonstrates that increased AcP signaling, specifically at the synapse, underlies the augmented vulnerability to cognitive impairment by IL-1{beta} that occurs with age.
