RETRACTED ARTICLE: APP binds DR6 to trigger axon pruning and neuron death via distinct caspases

Naturally occurring axonal pruning and neuronal cell death help to sculpt neuronal connections during development, but their mechanistic basis remains poorly understood. Here we report that β-amyloid precursor protein (APP) and death receptor 6 (DR6, also known as TNFRSF21) activate a widespread caspase-dependent self-destruction program. DR6 is broadly expressed by developing neurons, and is required for normal cell body death and axonal pruning both in vivo and after trophic-factor deprivation in vitro . Unlike neuronal cell body apoptosis, which requires caspase 3, we show that axonal degeneration requires caspase 6, which is activated in a punctate pattern that parallels the pattern of axonal fragmentation. DR6 is activated locally by an inactive surface ligand(s) that is released in an active form after trophic-factor deprivation, and we identify APP as a DR6 ligand. Trophic-factor deprivation triggers the shedding of surface APP in a β-secretase (BACE)-dependent manner. Loss- and gain-of-function studies support a model in which a cleaved amino-terminal fragment of APP (N-APP) binds DR6 and triggers degeneration. Genetic support is provided by a common neuromuscular junction phenotype in mutant mice. Our results indicate that APP and DR6 are components of a neuronal self-destruction pathway, and suggest that an extracellular fragment of APP, acting via DR6 and caspase 6, contributes to Alzheimer’s disease. Cell death: checks and balances During embryonic development, nerve cells are made in excess numbers, and many of these neurons and their long extensions (axons) are then culled in a phase of natural degeneration. Nikolaev et al . now identify the apoptosis-inducing protein DR6 (death receptor 6) as a regulator of this process, acting by binding to APP (β-amyloid precursor protein), a transmembrane protein of unknown function that has been implicated in Alzheimer's disease through human genetics. Unlike classical neuronal apoptosis, which requires caspase 3, DR6/APP-induced degeneration requires caspase 6 activation. This work suggests that an extracellular fragment of APP, acting via DR6 and caspase 6, may contribute to neural degeneration in Alzheimer's disease.