Journal
NEUROBIOLOGY OF AGING
Volume 29, Issue 9, Pages 1380-1393Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2007.02.027
Keywords
IL-1 beta; BDNF; signal transduction; cortical neurons
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Funding
- NIA NIH HHS [P01-AG-000538, P01 AG000538] Funding Source: Medline
- NATIONAL INSTITUTE ON AGING [P01AG000538] Funding Source: NIH RePORTER
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The expression of IL-1 is elevated in the CNS in diverse neurodegenerative disorders, including Alzheimer's disease. The hypothesis was tested that IL-1 beta renders neurons vulnerable to degeneration by interfering with BDNF-induced neuroprotection. In trophic support-deprived neurons, IL-1 beta 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 PLC gamma, was decreased. Activation of CREB, a target of these signaling pathways, was severely depressed by IL-1 beta. As the cytokine did not influence TrkB receptor and PLC gamma activation, IL-1 beta might have interfered with BDNF signaling at the docking step conveying activation to the PI3-K/Akt and Ras/MAPK pathways. Indeed, IL-1 beta suppressed the activation of the respective scaffolding proteins IRS-1 and She; 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-1 beta places neurons at risk by interfering with BDNF signaling involving a ceramide-associated mechanism. (C) 2007 Elsevier Inc. All rights reserved.
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