β-Amyloid 1-42 induces physiological transcriptional regulation of BACE1

Alessandra Piccini, Roberta Borghi, Michela Guglielmotto, Elena Tamagno, Gabriella Cirmena, Anna Garuti, Valeria Pollero, Sergio Cammarata, Michele Fornaro, Massimo Messa, Laura Colombo, Mario Salmona, George Perry, Massimo Tabaton

Research output: Contribution to journalArticle

Abstract

The pathogenesis of Alzheimer's disease (AD) is only partially understood. β-amyloid (Aβ) is physiologically generated by sequential cleavage of its precursor protein by the β- and the γ-secretase and it is normally disposed of. In Alzheimer's disease, Aβ is excessively produced or less dismissed, but the hypothesis on its physiological and pathological role are heterogeneous and often discordant. It has been described a positive feedback loop from the γ- to the β-secretase cleavages of Aβ precursor protein, which is activated by mutations of Presenilin 1 (PS1), the catalytic core of the γ-secretase. These findings show that Aβ precursor protein as well the activity of the γ-secretase are required to obtain the up-regulation of β-secretase which is induced by Presenilin 1 mutations. Then, Aβ 1-42 is the Aβ precursor protein derivative that up-regulates the expression of β-secretase, and c-jun N-terminal kinase (JNK)/c-Jun and ERK1/2 are involved. Here, we describe the activation of β-secretase and c-jun N-terminal kinase related proteins by monomeric Aβ 1-42, defining the conditions that most efficiently strike the described signaling without producing toxicity. Taken together these data imply that monomeric Aβ 1-42, at non-toxic concentrations and time frames, are able to induce a signaling pathway that leads to transcriptional activation of β-secretase.

Original languageEnglish
Pages (from-to)1023-1031
Number of pages9
JournalJournal of Neurochemistry
Volume122
Issue number5
DOIs
Publication statusPublished - Sep 2012

Keywords

  • β-amyloid
  • β-secretase
  • γ-secretase
  • aggregation
  • Alzheimer's disease
  • Presenilins

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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    Piccini, A., Borghi, R., Guglielmotto, M., Tamagno, E., Cirmena, G., Garuti, A., Pollero, V., Cammarata, S., Fornaro, M., Messa, M., Colombo, L., Salmona, M., Perry, G., & Tabaton, M. (2012). β-Amyloid 1-42 induces physiological transcriptional regulation of BACE1. Journal of Neurochemistry, 122(5), 1023-1031. https://doi.org/10.1111/j.1471-4159.2012.07834.x