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Evolving evidence suggests that brain inflammation and the buildup of proinflammatory cytokines increases the risk for cognitive decline and cognitive dysfunction. Interleukin-1β (IL-1β), acting via poorly understood mechanisms, appears to be a key cytokine in causing these deleterious effects along with a presumably related loss of LTP-type synaptic plasticity. We hypothesized that IL-1β disrupts BDNF signaling cascades and thereby impairs the formation of filamentous actin (F-actin) in dendritic spines, an event that is essential for the stabilization of LTP. Actin polymerization in spines requires phosphorylation of the filament severing protein cofilin and is modulated by expression of the immediate early gene product Arc. Using rat organotypic hippocampal cultures, we found that IL-1β suppressed BDNF-dependent regulation of Arc and phosphorylation of cofilin and CREB, a transcription factor regulating Arc expression. IL-1β appears to act on BDNF signal transduction by impairing the phosphorylation of insulin receptor substrate 1 (IRS-1), a protein which couples activation of the BDNF receptor TrkB to downstream signaling pathways regulating CREB, Arc, and cofilin. IL-1β upregulated p38 MAPK, and inhibiting p38 MAPK prevented IL-1β from disrupting BDNF signaling. IL-1β also prevented the formation of F-actin in spines and impaired the consolidation, but not induction, of BDNF-dependent LTP in acute hippocampal slices. The suppressive effect of IL-1β on F-actin and LTP was prevented by inhibiting p38 MAPK. These findings define a new mechanism for the action of IL-1β on LTP and point to a potential therapeutic target to restore synaptic plasticity.

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The accumulation of ␤-amyloid (A␤) is one of the etiological factors in Alzheimer's disease (AD). It has been assumed that the underlying mechanism involves a critical role of A␤-induced neurodegeneration. However, low levels of A␤, such as will accumulate during the course of the disease, may interfere with neuronal function via mechanisms other than those involving neurodegeneration. We have been testing, therefore, the hypothesis that A␤ at levels insufficient to cause degeneration (

The expression of IL-1 is elevated in the CNS in diverse neurodegenerative disorders, including Alzheimer's disease. The hypothesis was tested that IL-1β renders neurons vulnerable to degeneration by interfering with BDNF-induced neuroprotection. In trophic support-deprived neurons, IL-1β compromised the PI3-K/Akt pathway-mediated protection by BDNF and suppressed Akt activation. The effect was specific as in addition to Akt, the activation of MAPK/ ERK, but not PLCγ, was decreased. Activation of CREB, a target of these signaling pathways, was severely depressed by IL-1β. As the cytokine did not influence TrkB receptor and PLCγ activation, IL-1β might have interfered with BDNF signaling at the docking step conveying activation to the PI3-K/Akt and Ras/MAPK pathways. Indeed, IL-1β suppressed the activation of the respective scaffolding proteins IRS-1 and Shc; this effect might involve ceramide generation. IL-1-induced interference with BDNF neuroprotection and signal transduction was corrected, in part, by ceramide production inhibitors and mimicked by the cell-permeable C2-ceramide. These results suggest that IL-1β places neurons at risk by interfering with BDNF signaling involving a ceramide-associated mechanism. Keywords IL-1β; BDNF; signal transduction; cortical neuronsInterleukin-1 (IL-1) is a pluripotent proinflammatory cytokine that is a potent activator of host defense responses to infection and injury both in the periphery and the CNS [59]. However, IL-1 can also exacerbate damage in the CNS resulting from acute insults, such as © 2007 Elsevier Inc. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript cerebral ischemia and trauma, and circumstantial evidence is consistent with a similar role in chronic neurological diseases, such as multiple sclerosis, Parkinson's disease and Alzheimer's disease (AD) [48]. Furthermore, recent genetic studies highlighted the relevance of IL-1 in AD pathogenesis, showing that specific polymorphisms in the IL-1 gene cluster are associated with greatly increased risk for AD, especially for the earlier onset of the disease [23,50]. The view that inflammatory processes play an important role in pathogenesis has been supported by epidemiological studies, showing that certain antiinflammatory drugs result in a slower progression of the disease [2,8,43,77] and in transgenic AD models decrease the number of dystrophic neurites, activated microglia and IL-1 expression [35], although such drugs also modulate the production of the a...

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

Background: Autophagy is essential for normal neuron maintenance but can also promote death. Results: Brain-derived neurotrophic factor (BDNF) increases autophagosome formation but prevents excessive autophagic degradation by activating the mammalian target of rapamycin (mTOR). Conclusion: BDNF-dependent neuron survival requires suppression of autophagic flux, which was impaired by both rapamycin and interleukin-1␤ (IL-1␤). Significance: mTOR inhibition subverts BDNF survival signals.

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