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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-β protein precursor (AβPP) in neurodegeneration, a role that appears completely independent of amyloid-β (Aβ) 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 AβPP 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 AβPP (NAβPP) binds DR6, it sets off an apoptotic cascade in embryonic spinal neurons that targets both axons and cell bodies. The work indicates that N-AβPP 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 AβPP is a ligand for DR6 came as a complete surprise, and finding that AβPP 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 data, biochemical, cell biological, etc., and I do not doubt that it is relevant for AβPP biology,” said Bart De Strooper, University of Leuven, Belgium, who was at the meeting. He was not involved in the study. “Of course, when you have this type of data I think it is fair to ask how relevant it is for Alzheimer’s disease. I think it is too early to say if it is equivalent to the amyloid hypothesis, for example, because there is no human or clinical data,” he cautioned. Tessier-Lavigne and colleagues identified the NAβPP/DR6 interaction when studying neuronal development. The embryo is a tough environment for new neurons with many more being formed than typically needed. Those that do not make proper connections are eventually weeded out by a process that involves axonal pruning and cell death. First author Anatoly Nikolaev and colleagues found that DR6 plays a key role in this process, kicking off an apoptotic pathway in commissural, motor, and sensory neurons that depends on activation of caspase 6 in axons and caspase 3 in the soma only [1]. Nikolaev and colleagues mimicked this axon degeneration by withdrawing trophic support (such as nerve growth factor, or NGF) from neurons in culture, but if they blocked DR6 at the same time – with an antibody, by knocking it down with RNAi, or by genetic knockout – they were able to prevent axonopathy and cell death. Collaborating with Todd McLaughlin and Dennis O’Leary at the Salk Institute, they also showed that DR6 regulates neuron death and axonal pruning not just in cell culture, but also in vivo in a mouse model.

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