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Synapse-specific IL-1 receptor subunit reconfiguration augments vulnerability to IL-1β in the aged hippocampus

Academic Article
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Overview

authors

  • Prieto, G. A.
  • Snigdha, S.
  • Baglietto-Vargas, D.
  • Smith, E. D.
  • Berchtold, N. C.
  • Tong, L.
  • Ajami, Dariush
  • LaFerla, F. M.
  • Rebek Jr., Julius
  • Cotman, C. W.

publication date

  • September 2015

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

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.

subject areas

  • Age Factors
  • Animals
  • Blotting, Western
  • Brain-Derived Neurotrophic Factor
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Hippocampus
  • Interleukin-1 Receptor Accessory Protein
  • Interleukin-1beta
  • Long-Term Potentiation
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Neuronal Plasticity
  • Neurons
  • RNA Interference
  • Rats, Sprague-Dawley
  • Receptors, Interleukin-1 Type I
  • Signal Transduction
  • Synapses
  • Synaptosomes
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Research

keywords

  • AcP
  • AcPb
  • LTP
  • neuroinflammation
  • receptor sensitivity
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Identity

PubMed Central ID

  • PMC4568670

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.1514486112

PubMed ID

  • 26305968
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Additional Document Info

start page

  • E5078

end page

  • E5087

volume

  • 112

issue

  • 36

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