title: Synapse-specific IL-1 receptor subunit reconfiguration augments vulnerability to IL-1β in the aged hippocampus.
abstract: In the aged brain, synaptic plasticity and memory show increased vulnerability to impairment by the inflammatory cytokine interleukin 1β (IL-1β). In this study, we evaluated the possibility that synapses may directly undergo maladaptive changes with age that augment sensitivity to IL-1β impairment. In hippocampal neuronal cultures, IL-1β 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-1β. To evaluate whether synapses develop a similar heightened sensitivity to IL-1β with age, we used an assay to track long-term potentiation (LTP) in synaptosomes. We found that IL-1β impairs LTP directly at the synapse and that sensitivity to IL-1β is augmented in aged hippocampal synapses. The increased synaptic sensitivity to IL-1β 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-1β levels drives a shift in IL-1 receptor configuration, thus heightening the sensitivity to IL-1β. Accordingly, selective blocking of AcP-dependent signaling with Toll-IL-1 receptor domain peptidomimetics prevented IL-1β-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-1β that occurs with age.
authors: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697; cwcotman@uci.edu aleph.prieto@uci.edu jrebek@scripps.edu.
authors: G Aleph
authors: GA
authors: Prieto
authors: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697;
authors: Shikha
authors: S
authors: Snigdha
authors: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697;
authors: David
authors: D
authors: Baglietto-Vargas
authors: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697;
authors: Erica D
authors: ED
authors: Smith
authors: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697;
authors: Nicole C
authors: NC
authors: Berchtold
authors: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697;
authors: Liqi
authors: L
authors: Tong
authors: Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037;
authors: Dariush
authors: D
authors: Ajami
authors: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697;
authors: Frank M
authors: FM
authors: LaFerla
authors: Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037; Department of Chemistry, Fudan University, Shanghai, 200433 China cwcotman@uci.edu aleph.prieto@uci.edu jrebek@scripps.edu.
authors: Julius
authors: J
authors: Rebek
authors: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697; cwcotman@uci.edu aleph.prieto@uci.edu jrebek@scripps.edu.
authors: Carl W
authors: CW
authors: Cotman
mesh_terms: D000367:Age Factors; D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D053577:Interleukin-1 Receptor Accessory Protein / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology*; D017774:Long-Term Potentiation / Q000187:drug effects; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D053577:Interleukin-1 Receptor Accessory Protein; D053583:Interleukin-1beta; D053573:Receptors, Interleukin-1 Type I
keywords: AcP; AcPb; LTP; neuroinflammation; receptor sensitivity