Netrin-1 interacts with amyloid precursor protein and regulates amyloid-β production

F. C. Lourenço, V. Galvan, J. Fombonne, V. Corset, F. Llambi, U. Müller, D. E. Bredesen, P. Mehlen

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

The β-amyloid precursor protein (APP) is an orphan transmembrane receptor whose physiological role is largely unknown. APP is cleaved by proteases generating amyloid-β (Aβ) peptide, the main component of the amyloid plaques that are associated with Alzheimer's disease. Here, we show that APP binds netrin-1, a multifunctional guidance and trophic factor. Netrin-1 binding modulates APP signaling triggering APP intracellular domain (AICD)-dependent gene transcription. Furthermore, netrin-1 binding suppresses Aβ peptide production in brain slices from Alzheimer model transgenic mice. In this mouse model, decreased netrin-1 expression is associated with increased Aβ concentration, thus supporting netrin-1 as a key regulator of Aβ production. Finally, we show that netrin-1 brain administration in Alzheimer model transgenic mice may be associated with an amelioration of the Alzheimer's phenotype.

Original languageEnglish (US)
Pages (from-to)655-663
Number of pages9
JournalCell Death and Differentiation
Volume16
Issue number5
DOIs
StatePublished - 2009
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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