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PMID: 19225519 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.

Nature ·Vol. 457 ·No. 7232 ·2009-02-19 ·Pages 981-9

Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M

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.

MeSH Terms
Alzheimer Disease/metabolism Amyloid beta-Protein Precursor/chemistry,metabolism Animals Axons/metabolism Caspase 3/metabolism Caspase 6/metabolism Caspases/metabolism Cell Death Ligands Mice Neurons/cytology,metabolism Peptide Fragments/chemistry,metabolism Protein Binding Receptors, Tumor Necrosis Factor/metabolism Signal Transduction bcl-2-Associated X Protein/genetics,metabolism
Chemicals
Amyloid beta-Protein Precursor Bax protein, mouse Ligands Peptide Fragments Receptors, Tumor Necrosis Factor Tnfrsf21 protein, mouse bcl-2-Associated X Protein Caspase 3 Caspase 6 Caspases
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Nikolaev Anatoly
Division of Research, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
McLaughlin Todd
O'Leary Dennis D M
Tessier-Lavigne Marc
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature07767
Published
2009-02-19
Pages
981-9
Language
English
Region
England
NLM ID
0410462
PMCID
PMC2677572
Subset
IM
Grants
NIA NIH HHS · R01 AG025970 · United States
NEI NIH HHS · R01 EY007025 · United States
NEI NIH HHS · R01 EY007025-24 · United States
NEI NIH HHS · R01 EY07025 · United States
Corrections
CommentIn
PMID: 19225511
External Links
PubMed source DOI: 10.1038/nature07767 PMC Full Text View journal details
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