RETRACTED ARTICLE: APP binds DR6 to trigger axon pruning and neuron death via distinct caspases
Open accessAbstract
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.
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The N-terminal fragment of APP derived from sAPPβ may be toxic, can bind death receptor 6, and mediates axonal pruning and neuronal cell death.
“In contrast, N-terminal fragment of APP derived from sAPPβ may be toxic, where it can bind death receptor 6 and mediate axonal pruning and neuronal cell death [26].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [26]
Additional APP cleavage products are capable of causing toxicity independent of Aβ.
“These additional APP cleavage products are also capable of causing toxicity independent of Aβ [45, 105].”
From Alzheimer's disease: experimental models and reality (2017) · cites this paper as [105]
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“Resulting aggregates are associated with local induction of caspase-6, which has been implicated in precipitating axonal degeneration (Guo et al., 2004; Nikolaev et al., 2009; Uribe et al., 2012).”
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- Authors
- Nikolaev, A., McLaughlin, T., O’Leary, D. D. M., & Tessier-Lavigne, M.
- Affiliations
- Genentech (US)
- Salk Institute for Biological Studies (US)
- ORCID
- Nikolaev, Anatoly
- Venue
- Nature
- Published
- 2009-02-19
- Volume
- 457
- Issue
- 7232
- Pages
- 981-989
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2677572
- OpenAlex
- W2045855955
- Cited by
- 992
- References
- 62
- Citations by year
- 2026: 12 · 2025: 15 · 2024: 20 · 2023: 32 · 2022: 27 · 2021: 33 · 2020: 45 · 2019: 49 · 2018: 40 · 2017: 56 · 2016: 56 · 2015: 59 · 2014: 82 · 2013: 94 · 2012: 102
- FWCI
- 50.38
- Type
- journal article
- Language
- en
- Status
- Retracted
- Update notices
- retraction (2023-12-18)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Aging (R01AG025970)
- National Eye Institute (R01 EY 07025, R01EY007025)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Keywords
- APP, death receptor 6, axon pruning, neuronal cell death, caspase-6, caspase-3, trophic factor deprivation, BACE, Alzheimer's disease, neuromuscular junction, axonal degeneration, neuronal apoptosis
- MeSH terms
- Alzheimer Disease, Animals, Axons, Ligands, Neurons, Peptide Fragments, Protein Binding, Signal Transduction, Amyloid beta-Protein Precursor, Cell Death, Receptors, Tumor Necrosis Factor, Caspases, bcl-2-Associated X Protein, Mice, Caspase 3, Caspase 6
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