Netrin-1 as a ligand for APP receptor: molecular mechanism and implication in Alzheimer disease – APPNET

Despite the extensive research on Alzheimer's disease (AD) since its first description in 1907-including the sequencing of Aß peptide in 1984 and cloning of its precursor, APP (ß-amyloid precursor protein), in 1987-little is known about potential ligand interactions with APP, or about any associated ligand-dependent downstream signaling. During the course of the previous ANR "neuroscience", P. Mehlen's laboratory identified the guidance cue and trophic factor netrin-1 as a ligand for APP. They showed that this interaction affects APP signaling (including increased transcriptional activity of the APP intracellular domain (AICD)) and they showed that APP is required for netrin-1 function during growth of cortical neurons during development. Of great interest, netrin-1 binding to APP was then shown, both in vitro and in vivo to inhibit the generation of the Aß peptide that is key in AD (Patent CNRS/The Buck Institute for Age Research, n° 00532-050).
The identification of netrin-1 as a potential ligand for APP raises many questions regarding the potential role(s) of netrin-dependent APP signal transduction in neuronal development and degeneration but it may have also crucial importance in term of putative therapeutic development. Indeed, it would be of great interest to develop a compound that mimics netrin-1 as a candidate drug against AD. In the current application, two complementary partners (cell biology and animal models versus protein structure) propose to examine some of the critical questions related to the importance of netrin-1 in APP function and to bring this observation closer to drug development. First as a basic question, we would like to assay whether APP behaves as netrin-1 dependence receptor, that is to say that netrin-1, by interacting with APP, inhibits the known pro-apoptotic activity of APP, an activity that we believe is associated, in combination with Aß toxicity, with AD progression. Second we would like to demonstrate that netrin-1 controls not only Ab formation in AD mouse model but also the different hallmarks of the AD pathology. Third, we would like to determine the structure of the interaction APP/netrin-1 in order to define, using in silico screens and an high-through-put screen for small molecules, lead compounds that may mimic netrin-1 or that may increase netrin-1/APP interaction and as consequence may lead to an improvement of AD.
The project presented in this ANR “MALZ” call will first provide more basic knowledge to the relative importance of netrin-1 in APP function. It shall (i) describe the nature of the interaction between netrin-1 and APP, (ii) precise whether netrin-1 not only affects Aß formation but also formation of another toxic fragment called C31 generated after caspase cleavage of APP, and (iii) show whether netrin-1 level affects AD phenotype (and not only Aß formation) in an AD mouse model. This basic knowledge shall then be used to predict, design or characterize lead compounds that may in turn inhibit/delay AD progression.