Keystone Symposium, Neurodegenerative Diseases: New Molecular Mechanisms 17–22 February 2009

On Wednesday of the meeting, debate over the last plenary talk continued around the dinner table and well into the poster session. Marc Tessier-Lavigne, Genentech Inc., San Francisco, California, described a novel role for amyloid- protein precursor (APP) in neurodegeneration, a role that appears completely independent of amyloid- (A) toxicity and that might finally explain why only certain neurons bear the brunt of Alzheimer's disease (AD) pathology. Tessier-Lavigne reported that the extracellular domain of APP serves as a ligand for death receptor 6 (DR6), an orphan member of the tumor necrosis factor receptor superfamily. He showed that when the N-terminus of APP (N-APP) binds DR6, it sets off an apoptotic cascade in embryonic spinal neurons that targets both axons and cell bodies. The work indicates that N-APP has a role in axonal pruning and neural cell death in development, but it also raises the possibility that similar events occur in mature neurons in the brain. "Finding that an N-terminal fragment of APP is a ligand for DR6 came as a complete surprise, and finding that APP is involved in a self-destruction mechanism like this immediately suggested that perhaps it could contribute to Alzheimer's disease," said Tessier-Lavigne in an interview with this reporter after the talk. The study was coincidentally published in Wednesday's Nature. "This is very intriguing. I think the story is very convincing because there is a lot of very complementary