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: 8.18). 02/2009; 16(5):655-63. DOI: 10.1038/cdd.2008.191
Source: PubMed


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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    • "In previous work, the same group showed that netrin 1 can act as a functional ligand for APP and negatively regulates the formation of Aβ (Lourenço et al., 2009). Based on these studies, the authors proposed that DCC acts as a modulator and APP as a receptor for netrin 1, in order to maintain proper guidance for commissural axons. "
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    ABSTRACT: Interest in the amyloid precursor protein (APP) has increased in recent years due to its involvement in Alzheimer's disease. Since its molecular cloning, significant genetic and biochemical work has focused on the role of APP in the pathogenesis of this disease. Thus far, however, these studies have failed to deliver successful therapies. This suggests that understanding the basic biology of APP and its physiological role during development might be a crucial missing link for a better comprehension of Alzheimer's disease. Here, we present an overview of some of the key studies performed in various model organisms that have revealed roles for APP at different stages of neuronal development.
    Development 07/2014; 141(13):2543-8. DOI:10.1242/dev.108712 · 6.46 Impact Factor
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    • "Also, reelin binding to the E1 domain enhances the nonamyloidogenic processing of APP (Hoe et al., 2006, 2009). Finally, netrin reportedly interacts with APP within the Ab domain, and this interaction results in reduced Ab generation (Lourenço et al., 2009). The adhesive properties of APP have also been linked to a tetrapeptide sequence RHDS within the N-terminus of the Ab peptide, which promotes cell adhesion in an integrin-like manner (Ghiso et al., 1992). "
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    ABSTRACT: A role of amyloid β (Aβ) peptide aggregation and deposition in Alzheimer's disease (AD) pathogenesis is widely accepted. Significantly, abnormalities induced by aggregated Aβ have been linked to synaptic and neuritic degeneration, consistent with the "dying-back" pattern of degeneration that characterizes neurons affected in AD. However, molecular mechanisms underlying the toxic effect of aggregated Aβ remain elusive. In the last 2 decades, a variety of aggregated Aβ species have been identified and their toxic properties demonstrated in diverse experimental systems. Concurrently, specific Aβ assemblies have been shown to interact and misregulate a growing number of molecular effectors with diverse physiological functions. Such pleiotropic effects of aggregated Aβ posit a mayor challenge for the identification of the most cardinal Aβ effectors relevant to AD pathology. In this review, we discuss recent experimental evidence implicating amyloid β precursor protein (APP) as a molecular target for toxic Aβ assemblies. Based on a significant body of pathologic observations and experimental evidence, we propose a novel pathologic feed-forward mechanism linking Aβ aggregation to abnormalities in APP processing and function, which in turn would trigger the progressive loss of neuronal connectivity observed early in AD.
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    • "Recent, complementary results argue that signaling events, some of which are mediated by the amyloid precursor protein (APP) itself, also play a crucial role in the development of the AD phenotype [2], [9], [10], [11], [12], [13]. Furthermore, APP has recently been shown to be a receptor for netrin-1 [13], an axon guidance and survival factor and to give rise to N-APP, a ligand for DR6 (death receptor 6) [14]. In addition, binding of the multimeric APP to Aβ oligomers has recently been shown to promote the proteolytic processing of APP and increase the production of the toxic Aβ and C-31 peptides [15]. "
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