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• APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
• Citation:
  Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
  

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

  Nature. 2009 Feb 19;457(7232):981-9
  [PubMed] [Alzforum]
• Source For Statements:
  • DR6 is activated locally by an inactive surface ligand(s) that is released in an active form after trophic-factor deprivation.

    SHOW Details   Supporting(1)     Genes/Proteins: (1)

    Experimental Approach: Mechanism - molecular and cell
    Pathogenic Narrative Tags: Perturbation
    Supporting Evidence
    

    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9

    Genes/Proteins
    

    • Gene: Tnfrsf21 tumor necrosis factor receptor superfamily, member 21 [Mus musculus]
  • Trophic-factor deprivation triggers the shedding of surface APP in a β-secretase (BACE)-dependent manner.

    SHOW Details   Supporting(4)     Genes/Proteins: (2)

    Experimental Approach: Mechanism - molecular and cell,  
    Pathogenic Narrative Tags: Pathogenic event
    Supporting Evidence
    

    • Reinhard C, Hébert S, De Strooper B
      The amyloid-beta precursor protein: integrating structure with biological function.
      The EMBO journal. 2005 Dec 7;24(23):3996-4006
    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9
    • Walsh D, Minogue A, Sala Frigerio C, Fadeeva J, Wasco W, Selkoe D
      The APP family of proteins: similarities and differences.
      Biochemical Society transactions. 2007 Apr;35(Pt 2):416-20
    • Edwards P, Albert J, Sylvester M, Aharony D, Andisik D, Callaghan O, Campbell J, Carr R, Chessari G, Congreve M, Frederickson M, Folmer R, Geschwindner S, Koether G, Kolmodin K, Krumrine J, Mauger R, Murray C, Olsson L, Patel S, Spear N, Tian G
      Application of fragment-based lead generation to the discovery of novel, cyclic amidine beta-secretase inhibitors with nanomolar potency, cellular activity, and high ligand efficiency.
      Journal of medicinal chemistry. 2007 Nov 29;50(24):5912-25

    Genes/Proteins
    

    • Gene: Bace1 beta-site APP cleaving enzyme 1 [Mus musculus]
    • Gene: App amyloid beta (A4) precursor protein [Mus musculus]
  • In vivo, DR6 regulates lymphocyte development.

    SHOW Details   Supporting(2)     Genes/Proteins: (1)

    Experimental Approach: Mechanism - molecular and cell,  
    Pathogenic Narrative Tags: Perturbation
    Supporting Evidence
    

    • Zhao H, Yan M, Wang H, Erickson S, Grewal I, Dixit V
      Impaired c-Jun amino terminal kinase activity and T cell differentiation in death receptor 6-deficient mice.
      The Journal of experimental medicine. 2001 Nov 19;194(10):1441-8
    • Schmidt C, Liu J, Zhang T, Song H, Sandusky G, Mintze K, Benschop R, Glasebrook A, Yang D, Na S
      Enhanced B cell expansion, survival, and humoral responses by targeting death receptor 6.
      The Journal of experimental medicine. 2003 Jan 6;197(1):51-62

    Genes/Proteins
    

    • Protein: Tumor necrosis factor receptor superfamily member 21 [Mus musculus]
  • Acting via DR6 and caspase 6, the APP ectodomain contributes to Alzheimer’s disease in a paracrine prodegenerative manner in strong neurons, whereas APP also is activated in an autocrine prodegenerative manner in weak neurons.

    SHOW Details   Supporting(9)     Genes/Proteins: (5)

    Experimental Approach: Mechanism - molecular and cell,  
    Pathogenic Narrative Tags: Pathogenic event
    Supporting Evidence
    

    • Palmert M, Podlisny M, Witker D, Oltersdorf T, Younkin L, Selkoe D, Younkin S
      Antisera to an amino-terminal peptide detect the amyloid protein precursor of Alzheimer's disease and recognize senile plaques.
      Biochemical and biophysical research communications. 1988 Oct 14;156(1):432-7
    • Bertram L, Tanzi R
      Alzheimer's disease: one disorder, too many genes?
      Human molecular genetics. 2004 Apr 1;13 Spec No 1:R135-41
    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9
    • Guo H, Albrecht S, Bourdeau M, Petzke T, Bergeron C, LeBlanc A
      Active caspase-6 and caspase-6-cleaved tau in neuropil threads, neuritic plaques, and neurofibrillary tangles of Alzheimer's disease.
      The American journal of pathology. 2004 Aug;165(2):523-31
    • Matrone C, Ciotti M, Mercanti D, Marolda R, Calissano P
      NGF and BDNF signaling control amyloidogenic route and Abeta production in hippocampal neurons.
      Proceedings of the National Academy of Sciences of the United States of America. 2008 Sep 2;105(35):13139-44
    • Matrone C, Di Luzio A, Meli G, D'Aguanno S, Severini C, Ciotti M, Cattaneo A, Calissano P
      Activation of the amyloidogenic route by NGF deprivation induces apoptotic death in PC12 cells.
      Journal of Alzheimer's disease : JAD. 2008 Feb;13(1):81-96
    • Van Gool D, De Strooper B, Van Leuven F, Dom R
      Amyloid precursor protein accumulation in Lewy body dementia and Alzheimer's disease.
      Dementia (Basel, Switzerland). 1995;6(2):63-8
    • Horowitz P, Patterson K, Guillozet-Bongaarts A, Reynolds M, Carroll C, Weintraub S, Bennett D, Cryns V, Berry R, Binder L
      Early N-terminal changes and caspase-6 cleavage of tau in Alzheimer's disease.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2004 Sep 8;24(36):7895-902
    • Deppmann C, Mihalas S, Sharma N, Lonze B, Niebur E, Ginty D
      A model for neuronal competition during development.
      Science (New York, N.Y.). 2008 Apr 18;320(5874):369-73

    Genes/Proteins
    

    • Protein: Tumor necrosis factor receptor superfamily member 16 [Mus musculus]
    • Gene: Casp6 caspase 6 [Mus musculus]
    • Gene: Tnfrsf21 tumor necrosis factor receptor superfamily, member 21 [Mus musculus]
    • Protein: Microtubule-associated protein tau [Mus musculus]
    • Gene: App amyloid beta (A4) precursor protein [Mus musculus]
  • DR6—one of eight members of TNF receptor superfamily14 possesses a cytoplasmic death domain and is widely expressed by neurons as they differentiate and enter a pro-apoptotic state.

    SHOW Details 

    Experimental Approach: Mechanism - molecular and cell,   Genetics,  
    Pathogenic Narrative Tags: Initial condition
    
  • APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.

    SHOW Details 

    Description: This hypothesis suggests that APP and DR6 are components of a neuronal self-destruction pathway. An extracellular fragment of APP, acting via binding of DR6, activates a caspase 6 dependent axonal degeneration, thus contributes to Alzheimer’s disease.
    Contained Discourse: 22 Elements
    Experimental Approach:
    Pathogenic Narrative Tags:
    
  • DR6 function is required in axons for degeneration in vitro.

    SHOW Details   Supporting(2) 

    Experimental Approach: Genetics,   Mechanism - molecular and cell,   Animal models
    Pathogenic Narrative Tags: Perturbation
    Supporting Evidence
    

    • Campenot R, Walji A, Draker D
      Effects of sphingosine, staurosporine, and phorbol ester on neurites of rat sympathetic neurons growing in compartmented cultures.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 1991 Apr;11(4):1126-39
    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9
  • Degeneration can result ‘passively’ from the loss of support from trophic factors such as nerve growth factor (NGF).

    SHOW Details   Supporting(4)     Genes/Proteins: (1)

    Experimental Approach: Mechanism - molecular and cell
    Pathogenic Narrative Tags: Perturbation
    Supporting Evidence
    

    • Luo L, O'Leary D
      Axon retraction and degeneration in development and disease.
      Annual review of neuroscience. 2005;28:127-56
    • Buss R, Sun W, Oppenheim R
      Adaptive roles of programmed cell death during nervous system development.
      Annual review of neuroscience. 2006;29:1-35
    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9
    • Raff M, Whitmore A, Finn J
      Axonal self-destruction and neurodegeneration.
      Science (New York, N.Y.). 2002 May 3;296(5569):868-71

    Genes/Proteins
    

    • Gene: Ngf nerve growth factor [Mus musculus]
  • There is evidence for ‘active’ mechanisms of degeneration in which extrinsic signals trigger degeneration by means of pro-apoptotic receptors, including some members of the tumor necrosis factor (TNF) receptor superfamily such as p75NTR (also known as NGFR), Fas and TNFRSF1A (previously known as TNFR1).

    SHOW Details   Supporting(2)     Genes/Proteins: (3)

    Experimental Approach: Mechanism - molecular and cell,  
    Pathogenic Narrative Tags: Perturbation
    Supporting Evidence
    

    • Haase G, Pettmann B, Raoul C, Henderson C
      Signaling by death receptors in the nervous system.
      Current opinion in neurobiology. 2008 Jun;18(3):284-91
    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9

    Genes/Proteins
    

    • Gene: Ngfr nerve growth factor receptor (TNFR superfamily, member 16) [Mus musculus]
    • Gene: Tnf tumor necrosis factor [Mus musculus]
    • Gene: Tnfrsf1a tumor necrosis factor receptor superfamily, member 1a [Mus musculus]
  • Axonal degeneration requires a process that is distinct from neuronal cell body apoptosis, which requires caspase 3.

    SHOW Details   Consistent(1) 

    Experimental Approach: Pathophysiology,   Mechanism - molecular and cell,  
    Pathogenic Narrative Tags: Pathogenic event
    Consistent statements
    

    • Caspases are activated in AD brain and the caspase cleavage of tau can catalyze tangle formation. Cotman C 
  • Loss-of-function studies comparing phenotypes of App -/- Aplp2 -/- mice to DR6 -/- mice, support a model in which a cleaved amino-terminal fragment of APP (N-APP) binds DR6 and triggers degeneration.

    SHOW Details   Supporting(2)     Genes/Proteins: (3)

    Experimental Approach: Animal models,   Genetics,   Mechanism - molecular and cell
    Pathogenic Narrative Tags: Pathogenic event
    Supporting Evidence
    

    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9
    • Wang P, Yang G, Mosier D, Chang P, Zaidi T, Gong Y, Zhao N, Dominguez B, Lee K, Gan W, Zheng H
      Defective neuromuscular synapses in mice lacking amyloid precursor protein (APP) and APP-Like protein 2.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2005 Feb 2;25(5):1219-25

    Genes/Proteins
    

    • Gene: Aplp2 amyloid beta (A4) precursor-like protein 2 [Mus musculus]
    • Gene: Tnfrsf21 tumor necrosis factor receptor superfamily, member 21 [Mus musculus]
    • Gene: App amyloid beta (A4) precursor protein [Mus musculus]
  • Neuronal cell body degeneration requires the apoptotic effectors BAX and caspase 3.

    SHOW Details   Supporting(3)     Genes/Proteins: (2)

    Experimental Approach: Mechanism - molecular and cell,   Mechanism - biochemistry and structural biology,   Pathophysiology
    Pathogenic Narrative Tags: Pathogenic event
    Supporting Evidence
    

    • White F, Keller-Peck C, Knudson C, Korsmeyer S, Snider W
      Widespread elimination of naturally occurring neuronal death in Bax-deficient mice.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 1998 Feb 15;18(4):1428-39
    • Finn J, Weil M, Archer F, Siman R, Srinivasan A, Raff M
      Evidence that Wallerian degeneration and localized axon degeneration induced by local neurotrophin deprivation do not involve caspases.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2000 Feb 15;20(4):1333-41
    • Kuida K, Zheng T, Na S, Kuan C, Yang D, Karasuyama H, Rakic P, Flavell R
      Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice.
      Nature. 1996 Nov 28;384(6607):368-72

    Genes/Proteins
    

    • Gene: Bax BCL2-associated X protein [Mus musculus]
    • Gene: Casp3 caspase 3 [Mus musculus]
  • Developmental axonal degeneration similarly has many hallmarks of apoptosis— including blebbing, fragmentation, and phagocytic clearing of debris by neighboring cells.

    SHOW Details   Supporting(2) 

    Experimental Approach: Mechanism - molecular and cell,  
    Pathogenic Narrative Tags: Initial condition
    Supporting Evidence
    

    • Saxena S, Caroni P
      Mechanisms of axon degeneration: from development to disease.
      Progress in neurobiology. 2007 Oct;83(3):174-91
    • Luo L, O'Leary D
      Axon retraction and degeneration in development and disease.
      Annual review of neuroscience. 2005;28:127-56
  • APP is a DR6 ligand.

    SHOW Details   Supporting(5)     Genes/Proteins: (2)

    Experimental Approach: Mechanism - biochemistry and structural biology
    Pathogenic Narrative Tags: Initial condition
    Supporting Evidence
    

    • Hardy J, Selkoe D
      The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics.
      Science (New York, N.Y.). 2002 Jul 19;297(5580):353-6
    • Reinhard C, Hébert S, De Strooper B
      The amyloid-beta precursor protein: integrating structure with biological function.
      The EMBO journal. 2005 Dec 7;24(23):3996-4006
    • Haass C, Selkoe D
      Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide.
      Nature reviews. Molecular cell biology. 2007 Feb;8(2):101-12
    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9
    • Walsh D, Minogue A, Sala Frigerio C, Fadeeva J, Wasco W, Selkoe D
      The APP family of proteins: similarities and differences.
      Biochemical Society transactions. 2007 Apr;35(Pt 2):416-20

    Genes/Proteins
    

    • Gene: TNFRSF21 tumor necrosis factor receptor superfamily, member 21 [Homo sapiens]
    • Gene: Tnfrsf21 tumor necrosis factor receptor superfamily, member 21 [Mus musculus]
  • Genetic manipulations to inhibit apoptosis did not block axonal degeneration in some models.

    SHOW Details   Supporting(2)     Genes/Proteins: (1)

    Experimental Approach: Mechanism - molecular and cell
    Pathogenic Narrative Tags: Initial condition
    Supporting Evidence
    

    • Sagot Y, Dubois-Dauphin M, Tan S, de Bilbao F, Aebischer P, Martinou J, Kato A
      Bcl-2 overexpression prevents motoneuron cell body loss but not axonal degeneration in a mouse model of a neurodegenerative disease.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 1995 Nov;15(11):7727-33
    • Watts R, Hoopfer E, Luo L
      Axon pruning during Drosophila metamorphosis: evidence for local degeneration and requirement of the ubiquitin-proteasome system.
      Neuron. 2003 Jun 19;38(6):871-85

    Genes/Proteins
    

    • Gene: Bcl2 B-cell leukemia/lymphoma 2 [Mus musculus]
  • A prodegenerative DR6 ligand(s) is present on the neuronal surface and inactive, but is shed into medium in an active form after trophic deprivation, allowing it to bind and activate DR6.

    SHOW Details   Supporting(1)     Genes/Proteins: (2)

    Experimental Approach: Mechanism - molecular and cell,  
    Pathogenic Narrative Tags: Perturbation
    Supporting Evidence
    

    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9

    Genes/Proteins
    

    • Gene: TNFRSF21 tumor necrosis factor receptor superfamily, member 21 [Homo sapiens]
    • Gene: Tnfrsf21 tumor necrosis factor receptor superfamily, member 21 [Mus musculus]
  • Caspase 3 inhibitors block cell body but not axonal degeneration (reflecting higher activation of caspase 3 in cell bodies compared to axons.

    SHOW Details   Supporting(2)     Genes/Proteins: (2)

    Experimental Approach: Target validation,   Mechanism - biochemistry and structural biology,   Pathophysiology,   Mechanism - molecular and cell,  
    Pathogenic Narrative Tags: Pathogenic event
    Supporting Evidence
    

    • Plachta N, Annaheim C, Bissière S, Lin S, Rüegg M, Hoving S, Müller D, Poirier F, Bibel M, Barde Y
      Identification of a lectin causing the degeneration of neuronal processes using engineered embryonic stem cells.
      Nature neuroscience. 2007 Jun;10(6):712-9
    • Finn J, Weil M, Archer F, Siman R, Srinivasan A, Raff M
      Evidence that Wallerian degeneration and localized axon degeneration induced by local neurotrophin deprivation do not involve caspases.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2000 Feb 15;20(4):1333-41

    Genes/Proteins
    

    • Gene: Bax BCL2-associated X protein [Mus musculus]
    • Gene: Casp3 caspase 3 [Mus musculus]
  • DR6 functions in axonal pruning in vivo.

    SHOW Details   Supporting(2)     Genes/Proteins: (1)

    Experimental Approach: Mechanism - molecular and cell,   Genetics,   Animal models
    Pathogenic Narrative Tags: Perturbation
    Supporting Evidence
    

    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9
    • Luo L, O'Leary D
      Axon retraction and degeneration in development and disease.
      Annual review of neuroscience. 2005;28:127-56

    Genes/Proteins
    

    • Gene: Tnfrsf21 tumor necrosis factor receptor superfamily, member 21 [Mus musculus]
  • DR6 regulates axonal pruning.

    SHOW Details   Supporting(1)     Genes/Proteins: (1)

    Experimental Approach: Mechanism - molecular and cell
    Pathogenic Narrative Tags: Initial condition
    Supporting Evidence
    

    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9

    Genes/Proteins
    

    • Gene: Tnfrsf21 tumor necrosis factor receptor superfamily, member 21 [Mus musculus]
  • DR6 links passive and active apoptotic degeneration mechanisms, in which Casp3 mediates cell body degeneration requiring BAX, whereas Casp6, acting downstream of Bax, affects axon degeneration.

    SHOW Details   Supporting(1)     Genes/Proteins: (4)

    Experimental Approach: Mechanism - molecular and cell,   Genetics,   Animal models
    Pathogenic Narrative Tags: Perturbation
    Supporting Evidence
    

    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9

    Genes/Proteins
    

    • Protein: Tumor necrosis factor receptor superfamily member 21 [Mus musculus]
    • Gene: Bax BCL2-associated X protein [Mus musculus]
    • Gene: Casp6 caspase 6 [Mus musculus]
    • Gene: Casp3 caspase 3 [Mus musculus]
  • DR6 is an orphan receptor that triggers cell death in a Jun N-terminal kinase-dependent manner.

    SHOW Details   Supporting(2)     Genes/Proteins: (1)

    Experimental Approach: Mechanism - molecular and cell
    Pathogenic Narrative Tags: Initial condition
    Supporting Evidence
    

    • Bossen C, Ingold K, Tardivel A, Bodmer J, Gaide O, Hertig S, Ambrose C, Tschopp J, Schneider P
      Interactions of tumor necrosis factor (TNF) and TNF receptor family members in the mouse and human.
      The Journal of biological chemistry. 2006 May 19;281(20):13964-71
    • Pan G, Bauer J, Haridas V, Wang S, Liu D, Yu G, Vincenz C, Aggarwal B, Ni J, Dixit V
      Identification and functional characterization of DR6, a novel death domain-containing TNF receptor.
      FEBS letters. 1998 Jul 24;431(3):351-6

    Genes/Proteins
    

    • Gene: Bcl2 B-cell leukemia/lymphoma 2 [Mus musculus]
  • DR6 regulates neuronal death after trophic-factor deprivation in vitro.

    SHOW Details   Supporting(2)     Genes/Proteins: (1)

    Experimental Approach: Mechanism - molecular and cell,  
    Pathogenic Narrative Tags: Initial condition
    Supporting Evidence
    

    • Wang H, Tessier-Lavigne M
      En passant neurotrophic action of an intermediate axonal target in the developing mammalian CNS.
      Nature. 1999 Oct 21;401(6755):765-9
    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9

    Genes/Proteins
    

    • Gene: Tnfrsf21 tumor necrosis factor receptor superfamily, member 21 [Mus musculus]
• Supporting:
  • DR6 is activated locally by an inactive surface ligand(s) that is released in an active form after trophic-factor deprivation.

    SHOW Details   Supporting(1)     Genes/Proteins: (1)

    Experimental Approach: Mechanism - molecular and cell
    Pathogenic Narrative Tags: Perturbation
    Supporting Evidence
    

    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9

    Genes/Proteins
    

    • Gene: Tnfrsf21 tumor necrosis factor receptor superfamily, member 21 [Mus musculus]
  • Trophic-factor deprivation triggers the shedding of surface APP in a β-secretase (BACE)-dependent manner.

    SHOW Details   Supporting(4)     Genes/Proteins: (2)

    Experimental Approach: Mechanism - molecular and cell,  
    Pathogenic Narrative Tags: Pathogenic event
    Supporting Evidence
    

    • Reinhard C, Hébert S, De Strooper B
      The amyloid-beta precursor protein: integrating structure with biological function.
      The EMBO journal. 2005 Dec 7;24(23):3996-4006
    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9
    • Walsh D, Minogue A, Sala Frigerio C, Fadeeva J, Wasco W, Selkoe D
      The APP family of proteins: similarities and differences.
      Biochemical Society transactions. 2007 Apr;35(Pt 2):416-20
    • Edwards P, Albert J, Sylvester M, Aharony D, Andisik D, Callaghan O, Campbell J, Carr R, Chessari G, Congreve M, Frederickson M, Folmer R, Geschwindner S, Koether G, Kolmodin K, Krumrine J, Mauger R, Murray C, Olsson L, Patel S, Spear N, Tian G
      Application of fragment-based lead generation to the discovery of novel, cyclic amidine beta-secretase inhibitors with nanomolar potency, cellular activity, and high ligand efficiency.
      Journal of medicinal chemistry. 2007 Nov 29;50(24):5912-25

    Genes/Proteins
    

    • Gene: Bace1 beta-site APP cleaving enzyme 1 [Mus musculus]
    • Gene: App amyloid beta (A4) precursor protein [Mus musculus]
  • Acting via DR6 and caspase 6, the APP ectodomain contributes to Alzheimer’s disease in a paracrine prodegenerative manner in strong neurons, whereas APP also is activated in an autocrine prodegenerative manner in weak neurons.

    SHOW Details   Supporting(9)     Genes/Proteins: (5)

    Experimental Approach: Mechanism - molecular and cell,  
    Pathogenic Narrative Tags: Pathogenic event
    Supporting Evidence
    

    • Palmert M, Podlisny M, Witker D, Oltersdorf T, Younkin L, Selkoe D, Younkin S
      Antisera to an amino-terminal peptide detect the amyloid protein precursor of Alzheimer's disease and recognize senile plaques.
      Biochemical and biophysical research communications. 1988 Oct 14;156(1):432-7
    • Bertram L, Tanzi R
      Alzheimer's disease: one disorder, too many genes?
      Human molecular genetics. 2004 Apr 1;13 Spec No 1:R135-41
    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9
    • Guo H, Albrecht S, Bourdeau M, Petzke T, Bergeron C, LeBlanc A
      Active caspase-6 and caspase-6-cleaved tau in neuropil threads, neuritic plaques, and neurofibrillary tangles of Alzheimer's disease.
      The American journal of pathology. 2004 Aug;165(2):523-31
    • Matrone C, Ciotti M, Mercanti D, Marolda R, Calissano P
      NGF and BDNF signaling control amyloidogenic route and Abeta production in hippocampal neurons.
      Proceedings of the National Academy of Sciences of the United States of America. 2008 Sep 2;105(35):13139-44
    • Matrone C, Di Luzio A, Meli G, D'Aguanno S, Severini C, Ciotti M, Cattaneo A, Calissano P
      Activation of the amyloidogenic route by NGF deprivation induces apoptotic death in PC12 cells.
      Journal of Alzheimer's disease : JAD. 2008 Feb;13(1):81-96
    • Van Gool D, De Strooper B, Van Leuven F, Dom R
      Amyloid precursor protein accumulation in Lewy body dementia and Alzheimer's disease.
      Dementia (Basel, Switzerland). 1995;6(2):63-8
    • Horowitz P, Patterson K, Guillozet-Bongaarts A, Reynolds M, Carroll C, Weintraub S, Bennett D, Cryns V, Berry R, Binder L
      Early N-terminal changes and caspase-6 cleavage of tau in Alzheimer's disease.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2004 Sep 8;24(36):7895-902
    • Deppmann C, Mihalas S, Sharma N, Lonze B, Niebur E, Ginty D
      A model for neuronal competition during development.
      Science (New York, N.Y.). 2008 Apr 18;320(5874):369-73

    Genes/Proteins
    

    • Protein: Tumor necrosis factor receptor superfamily member 16 [Mus musculus]
    • Gene: Casp6 caspase 6 [Mus musculus]
    • Gene: Tnfrsf21 tumor necrosis factor receptor superfamily, member 21 [Mus musculus]
    • Protein: Microtubule-associated protein tau [Mus musculus]
    • Gene: App amyloid beta (A4) precursor protein [Mus musculus]
  • DR6 function is required in axons for degeneration in vitro.

    SHOW Details   Supporting(2) 

    Experimental Approach: Genetics,   Mechanism - molecular and cell,   Animal models
    Pathogenic Narrative Tags: Perturbation
    Supporting Evidence
    

    • Campenot R, Walji A, Draker D
      Effects of sphingosine, staurosporine, and phorbol ester on neurites of rat sympathetic neurons growing in compartmented cultures.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 1991 Apr;11(4):1126-39
    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9
  • Degeneration can result ‘passively’ from the loss of support from trophic factors such as nerve growth factor (NGF).

    SHOW Details   Supporting(4)     Genes/Proteins: (1)

    Experimental Approach: Mechanism - molecular and cell
    Pathogenic Narrative Tags: Perturbation
    Supporting Evidence
    

    • Luo L, O'Leary D
      Axon retraction and degeneration in development and disease.
      Annual review of neuroscience. 2005;28:127-56
    • Buss R, Sun W, Oppenheim R
      Adaptive roles of programmed cell death during nervous system development.
      Annual review of neuroscience. 2006;29:1-35
    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9
    • Raff M, Whitmore A, Finn J
      Axonal self-destruction and neurodegeneration.
      Science (New York, N.Y.). 2002 May 3;296(5569):868-71

    Genes/Proteins
    

    • Gene: Ngf nerve growth factor [Mus musculus]
  • There is evidence for ‘active’ mechanisms of degeneration in which extrinsic signals trigger degeneration by means of pro-apoptotic receptors, including some members of the tumor necrosis factor (TNF) receptor superfamily such as p75NTR (also known as NGFR), Fas and TNFRSF1A (previously known as TNFR1).

    SHOW Details   Supporting(2)     Genes/Proteins: (3)

    Experimental Approach: Mechanism - molecular and cell,  
    Pathogenic Narrative Tags: Perturbation
    Supporting Evidence
    

    • Haase G, Pettmann B, Raoul C, Henderson C
      Signaling by death receptors in the nervous system.
      Current opinion in neurobiology. 2008 Jun;18(3):284-91
    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9

    Genes/Proteins
    

    • Gene: Ngfr nerve growth factor receptor (TNFR superfamily, member 16) [Mus musculus]
    • Gene: Tnf tumor necrosis factor [Mus musculus]
    • Gene: Tnfrsf1a tumor necrosis factor receptor superfamily, member 1a [Mus musculus]
  • A focused effort to understand the functions of APP and the possible functions of Aβ should be a priority and the recent data showing that the extracellular domain of APP may have a role in axonal resculpting is an encouraging start in this direction.

    SHOW Details   Supporting(2)     Genes/Proteins: (3)

    Experimental Approach: Mechanism - biochemistry and structural biology,   Pathophysiology,  
    Pathogenic Narrative Tags: Initial condition
    Supporting Evidence
    

    • Hardy
      The amyloid hypothesis for Alzheimer's disease: a critical reappraisal.
      Journal of neurochemistry. 2009 May 18;
    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • Loss-of-function studies comparing phenotypes of App -/- Aplp2 -/- mice to DR6 -/- mice, support a model in which a cleaved amino-terminal fragment of APP (N-APP) binds DR6 and triggers degeneration.

    SHOW Details   Supporting(2)     Genes/Proteins: (3)

    Experimental Approach: Animal models,   Genetics,   Mechanism - molecular and cell
    Pathogenic Narrative Tags: Pathogenic event
    Supporting Evidence
    

    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9
    • Wang P, Yang G, Mosier D, Chang P, Zaidi T, Gong Y, Zhao N, Dominguez B, Lee K, Gan W, Zheng H
      Defective neuromuscular synapses in mice lacking amyloid precursor protein (APP) and APP-Like protein 2.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2005 Feb 2;25(5):1219-25

    Genes/Proteins
    

    • Gene: Aplp2 amyloid beta (A4) precursor-like protein 2 [Mus musculus]
    • Gene: Tnfrsf21 tumor necrosis factor receptor superfamily, member 21 [Mus musculus]
    • Gene: App amyloid beta (A4) precursor protein [Mus musculus]
  • APP is a DR6 ligand.

    SHOW Details   Supporting(5)     Genes/Proteins: (2)

    Experimental Approach: Mechanism - biochemistry and structural biology
    Pathogenic Narrative Tags: Initial condition
    Supporting Evidence
    

    • Hardy J, Selkoe D
      The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics.
      Science (New York, N.Y.). 2002 Jul 19;297(5580):353-6
    • Reinhard C, Hébert S, De Strooper B
      The amyloid-beta precursor protein: integrating structure with biological function.
      The EMBO journal. 2005 Dec 7;24(23):3996-4006
    • Haass C, Selkoe D
      Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide.
      Nature reviews. Molecular cell biology. 2007 Feb;8(2):101-12
    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9
    • Walsh D, Minogue A, Sala Frigerio C, Fadeeva J, Wasco W, Selkoe D
      The APP family of proteins: similarities and differences.
      Biochemical Society transactions. 2007 Apr;35(Pt 2):416-20

    Genes/Proteins
    

    • Gene: TNFRSF21 tumor necrosis factor receptor superfamily, member 21 [Homo sapiens]
    • Gene: Tnfrsf21 tumor necrosis factor receptor superfamily, member 21 [Mus musculus]
  • A prodegenerative DR6 ligand(s) is present on the neuronal surface and inactive, but is shed into medium in an active form after trophic deprivation, allowing it to bind and activate DR6.

    SHOW Details   Supporting(1)     Genes/Proteins: (2)

    Experimental Approach: Mechanism - molecular and cell,  
    Pathogenic Narrative Tags: Perturbation
    Supporting Evidence
    

    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9

    Genes/Proteins
    

    • Gene: TNFRSF21 tumor necrosis factor receptor superfamily, member 21 [Homo sapiens]
    • Gene: Tnfrsf21 tumor necrosis factor receptor superfamily, member 21 [Mus musculus]
  • DR6 functions in axonal pruning in vivo.

    SHOW Details   Supporting(2)     Genes/Proteins: (1)

    Experimental Approach: Mechanism - molecular and cell,   Genetics,   Animal models
    Pathogenic Narrative Tags: Perturbation
    Supporting Evidence
    

    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9
    • Luo L, O'Leary D
      Axon retraction and degeneration in development and disease.
      Annual review of neuroscience. 2005;28:127-56

    Genes/Proteins
    

    • Gene: Tnfrsf21 tumor necrosis factor receptor superfamily, member 21 [Mus musculus]
  • DR6 links passive and active apoptotic degeneration mechanisms, in which Casp3 mediates cell body degeneration requiring BAX, whereas Casp6, acting downstream of Bax, affects axon degeneration.

    SHOW Details   Supporting(1)     Genes/Proteins: (4)

    Experimental Approach: Mechanism - molecular and cell,   Genetics,   Animal models
    Pathogenic Narrative Tags: Perturbation
    Supporting Evidence
    

    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9

    Genes/Proteins
    

    • Protein: Tumor necrosis factor receptor superfamily member 21 [Mus musculus]
    • Gene: Bax BCL2-associated X protein [Mus musculus]
    • Gene: Casp6 caspase 6 [Mus musculus]
    • Gene: Casp3 caspase 3 [Mus musculus]
  • DR6 regulates axonal pruning.

    SHOW Details   Supporting(1)     Genes/Proteins: (1)

    Experimental Approach: Mechanism - molecular and cell
    Pathogenic Narrative Tags: Initial condition
    Supporting Evidence
    

    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9

    Genes/Proteins
    

    • Gene: Tnfrsf21 tumor necrosis factor receptor superfamily, member 21 [Mus musculus]
  • DR6 regulates neuronal death after trophic-factor deprivation in vitro.

    SHOW Details   Supporting(2)     Genes/Proteins: (1)

    Experimental Approach: Mechanism - molecular and cell,  
    Pathogenic Narrative Tags: Initial condition
    Supporting Evidence
    

    • Wang H, Tessier-Lavigne M
      En passant neurotrophic action of an intermediate axonal target in the developing mammalian CNS.
      Nature. 1999 Oct 21;401(6755):765-9
    • Nikolaev A, McLaughlin T, O'Leary D, Tessier-Lavigne M
      APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.
      Nature. 2009 Feb 19;457(7232):981-9

    Genes/Proteins
    

    • Gene: Tnfrsf21 tumor necrosis factor receptor superfamily, member 21 [Mus musculus]
• Created On: Mon, Jul 13 14:02:11 EDT 2009
• Last Modified On: Mon Jul 13 14:02:11 EDT 2009