ArticleNature2009
APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
Article in Nature, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It has been retracted, and should not be counted. Cited by 567 papers, 2 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
567 citing papers in PubMed, 2 syntheses or guidelines pooled it, 974 citations in OpenAlex.
- Pooled it
- Antibody-Based Therapeutic Interventions for Amyotrophic Lateral Sclerosis: A Systematic Literature Review.Frontiers in neuroscience · 2021Pooled it
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- The Intricate Role of Caspase-6 and Death Receptor-6 in Neurodegenerative Diseases.Cell biochemistry and biophysics · 2026Review
- Alzheimer's Disease Pathogenic Mechanisms: Linking Redox Homeostasis and Mitochondria-Associated Metabolic Pathways Through Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2).Antioxidants (Basel, Switzerland) · 2025Review
- Article
- Resilience mechanisms underlying Alzheimer's disease.Metabolic brain disease · 2025Review
- A Novel Systemic siDR6 Delivery System Based on DP7-C for the Treatment of Metastatic Lung Cancer.International journal of nanomedicine · 2025Article
- Article
- Activity-Dependent Synapse Refinement: From Mechanisms to Molecules.The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry · 2024Review
- Increased expression of the proapoptotic presenilin associated protein is involved in neuronal tangle formation in human brain.Scientific reports · 2024Article
- iPSC-induced neurons with the V337M MAPT mutation are selectively vulnerable to caspase-mediated cleavage of tau and apoptotic cell death.Molecular and cellular neurosciences · 2024Article
- Exploring caspase functions in mouse models.Apoptosis : an international journal on programmed cell death · 2024Review
- Endothelial DR6 in blood-brain barrier malfunction in Alzheimer's disease.Cell death & disease · 2024Article
- Neurodegeneration Biomarkers in Adult Spinal Muscular Atrophy (SMA) Patients Treated with Nusinersen.International journal of molecular sciences · 2024Article
- Amyloid Precursor Protein: A Regulatory Hub in Alzheimer's Disease.Aging and disease · 2024Review
- Article
- Rapamycin as a Potential Alternative Drug for Squamous Cell Gingiva Carcinoma (Ca9-22): A Focus on Cell Cycle, Apoptosis and Autophagy Genetic Profile.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Identification of TNFRSF21 as an inhibitory factor of osteosarcoma based on a necroptosis-related prognostic gene signature and molecular experiments.Cancer cell international · 2024Article
- Retraction Note: APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.Nature · 2024Article
507 more citing papers are in PubMed but not listed here.
Corrections and comments
- Retraction · 2023-12-18Concerns/Issues about Data · Concerns/Issues about Image · Duplication of/in Image · Investigation by Company/Institution · Investigation by Journal/Publisher · Original Data and/or Images not Provided and/or not Available · Unreliable Results and/or Conclusions · · See also: https://pubpeer.com/publications/B6410F2AF1398E6F379B244E7520A1
- Commented on by
- Retracted
Authors and funding
4 authors at 2 institutions in 1 country.
Funding
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.
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Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.