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Netrin-1 interacts with amyloid precursor protein and regulates amyloid-beta production.

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.

SUBMITTER: Lourenco FC

PROVIDER: S-EPMC2757418 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Netrin-1 interacts with amyloid precursor protein and regulates amyloid-beta production.

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

Cell death and differentiation 20090116 5

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 ...[more]

PMID: 19148186

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