期刊
CELL DEATH AND DIFFERENTIATION
卷 16, 期 5, 页码 655-663出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2008.191
关键词
Alzheimer's disease; netrin-1; amyloid-beta; amyloid precursor protein
资金
- Ligue Contre le Cancer
- fondation pour le Cerveau
- ARC
- ANR
- NIH [NS33376]
- Joseph Drown Foundation
- John Douglas French Foundation
- Alzheimer's Association
- Portuguese Science and Technology Foundation [POCI2010]
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS033376] Funding Source: NIH RePORTER
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.
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