title: APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
abstract: 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.
authors.affiliation: Division of Research, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Anatoly
authors.initials: A
authors.lastname: Nikolaev
authors.forename: Todd
authors.initials: T
authors.lastname: McLaughlin
authors.forename: Dennis D M
authors.initials: DD
authors.lastname: O'Leary
authors.forename: Marc
authors.initials: M
authors.lastname: Tessier-Lavigne
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D053178:Caspase 6 / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death; D008024:Ligands; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D015398:Signal Transduction; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; C494827:Bax protein, mouse; D008024:Ligands; D010446:Peptide Fragments; D018124:Receptors, Tumor Necrosis Factor; C485251:Tnfrsf21 protein, mouse; D051028:bcl-2-Associated X Protein; D053148:Caspase 3; D053178:Caspase 6; D020169:Caspases