Netrin-1 interacts with amyloid precursor protein and regulates amyloid-beta production.
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.
Lourenço
F C
FC
Apoptosis, Cancer and Development Laboratory - Equipe labellisée La Ligue, CNRS UMR5238, Centre Léon Bérard, University of Lyon, Lyon, France.
Galvan
V
V
Fombonne
J
J
Corset
V
V
Llambi
F
F
Müller
U
U
Bredesen
D E
DE
Mehlen
P
P
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000473:pathology; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009414:Nerve Growth Factors / Q000008:administration & dosage / Q000378:metabolism*; D000075388:Netrin-1; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000008:administration & dosage / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1