| First Author | Nikolaev A | Year | 2009 |
| Journal | Nature | Volume | 457 |
| Issue | 7232 | Pages | 981-9 |
| PubMed ID | 19225519 | Mgi Jnum | J:146602 |
| Mgi Id | MGI:3838040 | Doi | 10.1038/nature07767 |
| Citation | Nikolaev A, et al. (2009) APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. (RETRACTION Nature https://doi.org/10.1038/nature07767). Nature 457(7232):981-9 |
| abstractText | 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 beta-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 beta-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. |
