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

被引:71
作者
Lourenco, F. C. [1 ]
Galvan, V. [2 ]
Fombonne, J. [1 ]
Corset, V. [1 ]
Llambi, F. [1 ]
Mueller, U. [3 ]
Bredesen, D. E. [2 ]
Mehlen, P. [1 ,2 ]
机构
[1] Univ Lyon, CNRS, Ctr Leon Berard,Equipe Labellisee La Ligue, Apoptosis Canc & Dev Lab,UMR5238, F-69008 Lyon, France
[2] Buck Inst Age Res, Novato, CA 94945 USA
[3] Heidelberg Univ, IPMB, Heidelberg, Germany
关键词
Alzheimer's disease; netrin-1; amyloid-beta; amyloid precursor protein; ALZHEIMERS-DISEASE; INTRACELLULAR DOMAIN; NEURITE OUTGROWTH; TRANSGENIC MICE; NERVOUS-SYSTEM; APP; RECEPTOR; FE65; DCC; APOPTOSIS;
D O I
10.1038/cdd.2008.191
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 (A beta) 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 A beta peptide production in brain slices from Alzheimer model transgenic mice. In this mouse model, decreased netrin-1 expression is associated with increased A beta concentration, thus supporting netrin-1 as a key regulator of A beta 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.
引用
收藏
页码:655 / 663
页数:9
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