Molecular mechanisms involved in interleukin 1-beta (IL-1β)-induced memory impairment. Modulation by alpha-melanocyte-stimulating hormone (α-MSH)

Gonzalez, Patricia Verónica; Machado, Ivana Noelia; Vilcaes, Aldo Alejandro; Caruso, Carla Mariana; Roth, German A.; Schiöth, Helgi B.; Lasaga, Mercedes; Scimonelli, Teresa Nieves

doi:10.1016/j.bbi.2013.08.007

Cited by 52 publications

(40 citation statements)

References 66 publications

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“…Consistent with the in vitro finding that microglia-derived IL-1β can reduce spine density (59), our data demonstrate that hippocampal synapses contain the biochemical IL-1β-signaling pathway(s) impairing plasticity (e.g., p38) (29,54). To our knowledge, we demonstrate for the first time that AcP-dependent IL-1β signaling at the synapse can itself underlie the suppression of plasticity by IL-1β.…”

Section: Discussionsupporting

confidence: 73%

“…This finding is consistent with the notion that endogenous IL-1β at physiologically low levels may be essential for hippocampal memory function (51)(52)(53). Because p38 is a pivotal stress kinase downstream of the AcPdependent pathway (19) by which IL-1β inhibits hippocampaldependent memory (54), LTP (29,55), and BDNF signaling (29), we assessed p38 activation in size-gated synaptosomes from aged mice treated in accordance with the design used to evaluate OLM. Flow cytometry analysis showed that LPS significantly increased p-p38 levels in hippocampal synaptosomes.…”

Section: Acute Inflammation Impairs Hippocampal-dependent Memory Insupporting

confidence: 67%

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

Prieto

Snigdha

Baglietto‐Vargas

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

107

121

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In the aged brain, synaptic plasticity and memory show increased vulnerability to impairment by the inflammatory cytokine interleukin 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.AcP | AcPb | neuroinflammation | receptor sensitivity | LTP

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Section: Discussionsupporting

confidence: 73%

Section: Acute Inflammation Impairs Hippocampal-dependent Memory Insupporting

confidence: 67%

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

Prieto

Snigdha

Baglietto‐Vargas

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

107

121

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“…In other experimental models IL-1b was shown to modify some of the signaling molecules critically involved in memory reconsolidation. In these reports, IL-1b reduced glutamate release during LTP (Kelly et al, 2003), decreased ERK phosphorylation during memory consolidation (Gonzalez et al, 2013) and in activated microglia in culture (Saud et al, 2005) and also decreased zif268 expression in human epidermal keratinocytes (Lukiw et al, 1998). However, the molecular mechanism involved in the effect of IL-1b on memory reconsolidation has not yet been established.…”

Section: Introductionmentioning

confidence: 92%

“…The dorsal hippocampus was dissected as previously described and synaptosomes were purified on discontinuous Percoll gradients as described previously (Gonzalez et al, 2013). Briefly, synaptosomes sedimenting between 10% and 23% Percoll bands, were collected and diluted in a final volume of 10 ml of HEPES buffer medium consisting of 140 mM NaCl, 5 mM KCl, 5 mM NaHCO 3 , 1 mM MgCl 2 , 1.2 mM Na 2 HPO 4 , 10 mM glucose and 10 mM HEPES, pH 7.4 before centrifugation at 22,000g for 14 min at 4°C.…”

Section: Preparation Of Hippocampal Synaptosomesmentioning

confidence: 99%

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Interleukin-1β-induced memory reconsolidation impairment is mediated by a reduction in glutamate release and zif268 expression and α-melanocyte-stimulating hormone prevented these effects

Machado

Gonzalez

Vilcaes

et al. 2015

Brain, Behavior, and Immunity

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Age-Dependent Changes in the Activation and Regulation of Microglia

Cornejo

Bernhardi

2016

Advances in Experimental Medicine and Biology

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As we age, a large number of physiological and molecular changes affect the normal functioning of cells, tissues, and the organism as a whole. One of the main changes is the establishment of a state of systemic inflammatory activation, which has been termed "inflamm-aging"; a mild chronic inflammation of the aging organism that reduces the ability to generate an efficient response against stressor stimuli. As any other system, the nervous system undergoes these aging-related changes; the neuroinflammatory state depends mainly on the dysregulated activation of microglia, the innate immune cells of the central nervous system (CNS) and the principal producers of reactive oxygen species. As the brain ages, microglia acquire a phenotype that is increasingly inflammatory and cytotoxic, generating a hostile environment for neurons. There is mounting evidence that this process facilitates development of neurodegenerative diseases, for which the greatest risk factor is age. In this chapter, we will review key aging-associated changes occurring in the central nervous system, focusing primarily on the changes that occur in aging microglia, the inflammatory and oxidative stressful environment they establish, and their impaired regulation. In addition, we will discuss the effects of aged microglia on neuronal function and their participation in the development of neurodegenerative pathologies such as Parkinson's and Alzheimer's diseases.

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Molecular mechanisms involved in interleukin 1-beta (IL-1β)-induced memory impairment. Modulation by alpha-melanocyte-stimulating hormone (α-MSH)

Cited by 52 publications

References 66 publications

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

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

Interleukin-1β-induced memory reconsolidation impairment is mediated by a reduction in glutamate release and zif268 expression and α-melanocyte-stimulating hormone prevented these effects

Age-Dependent Changes in the Activation and Regulation of Microglia

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