NF-κB pathway: A target for preventing β-amyloid (Aβ)-induced neuronal damage and Aβ42 production

Alessandra Valerio, Flora Boroni, Marina Benarese, Ilenia Sarnico, Valentina Ghisi, Laura Grazia Bresciani, Marina Ferrario, Giuseppe Borsani, Pierfranco Spano, Marina Pizzi

Research output: Contribution to journalArticle

Abstract

Beta-amyloid (Aβ) peptides are key proteins in the pathophysiology of Alzheimer's disease (AD). While Aβ42 aggregates very rapidly to form early diffuse plaques, supplemental Aβ40 deposition is required to form mature neuritic plaques. We here investigated the role of nuclear factor-κB (NF-κB) pathway in Aβ40-mediated neuronal damage and amyloid pathology. In rat primary neurons and human postmitotic neuronal cells, the Aβ peptide induced a dose-dependent neuronal death, reduced the levels of the anti-apoptotic protein Bcl-XL, enhanced the cytosolic release of cytochrome c, and elicited the intracellular accumulation and secretion of Aβ42 oligomers. Moreover, Aβ40 activated the NF-κB pathway by selectively inducing the nuclear translocation of p65 and p50 subunits, and promoted an apoptotic profile of gene expression. As inhibitors of the NF-κB pathway, we tested the capability of a double-stranded κB decoy oligonucleotide, the anti-inflammatory drug aspirin and the selective IκB kinase 2 inhibitor, AS602868, to modify the Aβ40-mediated effects. These treatments, transiently applied before Aβ exposure, completely inhibited p50/p65 nuclear translocation and neuronal damage. The κB decoy also inhibited the Aβ-induced release of cytochrome c, restored the levels of Bcl-XL, and prevented intraneuronal accumulation and secretion of Aβ42. These results open up interesting perspectives on the development of novel strategies targeting out NF-κB p50/p65 dimers for pharmacological intervention in AD.

Original languageEnglish
Pages (from-to)1711-1720
Number of pages10
JournalEuropean Journal of Neuroscience
Volume23
Issue number7
DOIs
Publication statusPublished - Apr 2006

Keywords

  • Alzheimer's disease
  • Apoptosis
  • Human
  • Mouse
  • Transcription factors

ASJC Scopus subject areas

  • Neuroscience(all)

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    Valerio, A., Boroni, F., Benarese, M., Sarnico, I., Ghisi, V., Bresciani, L. G., Ferrario, M., Borsani, G., Spano, P., & Pizzi, M. (2006). NF-κB pathway: A target for preventing β-amyloid (Aβ)-induced neuronal damage and Aβ42 production. European Journal of Neuroscience, 23(7), 1711-1720. https://doi.org/10.1111/j.1460-9568.2006.04722.x