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Characterization of the signaling pathway downstream p75 neurotrophin receptor involved in β-amyloid peptide-dependent cell death

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Abstract

The accumulation of β-amyloid (Aβ) peptide is a key pathogenic event in Alzheimer’s disease. Previous studies have shown that Aβ peptide can damage neurons by activating the p75 neurotrophin receptor (p75NTR). However, the signaling pathway leading to neuronal cell death is not completely understood. By using a neuroblastoma cell line devoid of neurotrophin receptors and engineered to express either a full-length or a death domain (DD)-truncated form of p75NTR, we demonstrated that Aβ peptide activates the mitogen-activated protein kinases (MAPKs) p38 and c-Jun N-terminal kinase (JNK). We also found that Aβ peptide induces the translocation of nuclear factor-κB (NF-κB). These events depend on the DD of p75NTR. β-Amyloid (Aβ) peptide was found not to be toxic when the above interactors were inhibited, indicating that they are required for Aβ-induced neuronal cell death. p75 neurotrophin receptor (p75NTR)-expressing cells became resistant to Aβ toxicity when transfected with dominant-negative mutants of MAPK kinases 3, 4, or 6 (MKK3, MKK4, or MKK6), the inhibitor of κBα, or when treated with chemical inhibitors of p38 and JNK. Furthermore, p75NTR-expressing cells became resistant to Aβ peptide upon transfection with a dominant-negative mutant of p53. These results were obtained in the presence of normal p38 and JNK activation, indicating that p53 acts downstream of p38 and JNK. Finally, we demonstrated that NF-κB activation is dependent on p38 and JNK activation. Therefore, our data suggest a signaling pathway in which Aβ peptide binds to p75NTR and activates p38 and JNK in a DD-dependent manner, followed by NF-κB translocation and p53 activation.

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Authors and Affiliations

  1. Department of Pathology Section of General Pathology, University of Verona, Strada Le Grazie 8, 37134, Verona, Italy

    Claudio Costantini, Filippo Rossi & Vittorina Della-Bianca

  2. Department of Medicine and Public Health, Section of Pharmacology, University of Verona, P. le Scuro 10, 37134, Verona, Italy

    Elena Formaggio

  3. Department of Biology, University of Bologna, via Selmi 3, 40126, Bologna, Italy

    Roberto Bernardoni

  4. Department of Agricultural and Industrial Biotechnologies, University of Verona, Strada Le Grazie 15, 37134, Verona, Italy

    Daniela Cecconi

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  1. Claudio Costantini
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  2. Filippo Rossi
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  3. Elena Formaggio
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  4. Roberto Bernardoni
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  5. Daniela Cecconi
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  6. Vittorina Della-Bianca
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Correspondence to Claudio Costantini.

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Costantini, C., Rossi, F., Formaggio, E. et al. Characterization of the signaling pathway downstream p75 neurotrophin receptor involved in β-amyloid peptide-dependent cell death. J Mol Neurosci 25, 141–156 (2005). https://doi.org/10.1385/JMN:25:2:141

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  • DOI: https://doi.org/10.1385/JMN:25:2:141

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