Mutant presenilin 1 increases the expression and activity of BACE1

Luca Giliberto, Roberta Borghi, Alessandra Piccini, Rosa Mangerini, Sandro Sorbi, Gabriella Cirmena, Anna Garuti, Bernardino Ghetti, Fabrizio Tagliavini, Mohamed R. Mughal, Mark P. Mattson, Xiongwei Zhu, Xinglong Wang, Michela Guglielmotto, Elena Tamagno, Massimo Tabaton

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Mutations of the presenilin 1 (PS1) gene are the most common cause of early onset familial Alzheimer disease (FAD). PS1 mutations alter the activity of the γ-secretase on the β-amyloid precursor protein (APP), leading to selective overproduction of β-amyloid (Aβ) 42 peptides, the species that forms oligomers that may exert toxic effects on neurons. Here we show that PS1 mutations, expressed both transiently and stably, in non-neuronal and neuronal cell lines increase the expression and the activity of the β-secretase (BACE1), the rate-limiting step of Aβ production. Also, BACE1 expression and activity are elevated in brains of PS1 mutant knock-in mice compared with wild type littermates as well as in cerebral cortex of FAD cases bearing various PS1 mutations compared with in sporadic AD cases and controls. The up-regulation of BACE1 by PS1 mutations requires the γ-secretase cleavage of APP and is proportional to the amount of secreted Aβ42. Aβ42, and not AICD (APP intracellular domain), is indeed the APP derivative that mediates the overexpression of BACE1. The effect of PS1 mutations on BACE1 may contribute to determine the wide clinical and pathological phenotype of early onset FAD.

Original languageEnglish (US)
Pages (from-to)9027-9038
Number of pages12
JournalJournal of Biological Chemistry
Volume284
Issue number14
DOIs
StatePublished - Apr 3 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Giliberto, L., Borghi, R., Piccini, A., Mangerini, R., Sorbi, S., Cirmena, G., Garuti, A., Ghetti, B., Tagliavini, F., Mughal, M. R., Mattson, M. P., Zhu, X., Wang, X., Guglielmotto, M., Tamagno, E., & Tabaton, M. (2009). Mutant presenilin 1 increases the expression and activity of BACE1. Journal of Biological Chemistry, 284(14), 9027-9038. https://doi.org/10.1074/jbc.M805685200