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

Apoptosis, Cancer and Development Laboratory - Equipe labellisée La Ligue, CNRS UMR5238, Centre Léon Bérard, University of Lyon, Lyon, France.
Cell death and differentiation (Impact Factor: 8.39). 02/2009; 16(5):655-63. DOI: 10.1038/cdd.2008.191
Source: PubMed

ABSTRACT The beta-amyloid precursor protein (APP) is an orphan transmembrane receptor whose physiological role is largely unknown. APP is cleaved by proteases generating amyloid-beta (Abeta) 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 Abeta peptide production in brain slices from Alzheimer model transgenic mice. In this mouse model, decreased netrin-1 expression is associated with increased Abeta concentration, thus supporting netrin-1 as a key regulator of Abeta 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.

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