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• Acute gamma-secretase inhibition of nonhuman primate CNS shifts amyloid precursor protein (APP) metabolism from amyloid-beta production to alternative APP fragments without amyloid-beta rebound.
• Citation:
  Cook J, Wildsmith K, Gilberto D, Holahan M, Kinney G, Mathers P, Michener M, Price E, Shearman M, Simon A, Wang J, Wu G, Yarasheski K, Bateman R
  

  Acute gamma-secretase inhibition of nonhuman primate CNS shifts amyloid precursor protein (APP) metabolism from amyloid-beta production to alternative APP fragments without amyloid-beta rebound.

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 2010 May 12;30(19):6743-50
  [PubMed] [Alzforum]
• Source For Statements:
  • Single oral administration of two doses of the CNS-penetrant γ-secretase inhibitor (GSI), MK-0752 in healthy male CMP rhesus monkeys demonstrate a dose-related reduction of Aβ40 levels in plasma and CSF Aβ40 and Aβ42 followed by Aβ rebound above baseline in plasma but not in CSF.

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

    Experimental Approach: Mechanism - biochemistry and structural biology,   Target validation,   Animal models
    Pathogenic Narrative Tags: Perturbation
    Supporting Evidence
    

    • Cook J, Wildsmith K, Gilberto D, Holahan M, Kinney G, Mathers P, Michener M, Price E, Shearman M, Simon A, Wang J, Wu G, Yarasheski K, Bateman R
      Acute gamma-secretase inhibition of nonhuman primate CNS shifts amyloid precursor protein (APP) metabolism from amyloid-beta production to alternative APP fragments without amyloid-beta rebound.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2010 May 12;30(19):6743-50

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
  • In rhesus monkeys treated with a high dose of γ-secretase inhibitor (GSI) MK-0752 (240 mg/kg), levels of Aβ(1-14), Aβ(1-15), and Aβ(1-16) increased over vehicle levels, while levels of Aβ(1-17) decreased and these changes occurred concomitantly with an expected reduction in plasma Aβ40 and CSF Aβ40 and Aβ42, followed by peripheral but not central Aβ rebound effects.

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

    Experimental Approach: Target validation,   Mechanism - biochemistry and structural biology,   Animal models
    Pathogenic Narrative Tags: Perturbation
    Supporting Evidence
    

    • Cook J, Wildsmith K, Gilberto D, Holahan M, Kinney G, Mathers P, Michener M, Price E, Shearman M, Simon A, Wang J, Wu G, Yarasheski K, Bateman R
      Acute gamma-secretase inhibition of nonhuman primate CNS shifts amyloid precursor protein (APP) metabolism from amyloid-beta production to alternative APP fragments without amyloid-beta rebound.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2010 May 12;30(19):6743-50

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
  • The GSI MK-0752 reduction of CSF Aβ without a subsequent rebound suggests that in the absence of γ-secretase, the combined proteolytic cleavage of the Aβ precursor by β-secretase and α-secretase generates Aβ(1-14), Aβ(1-15), and Aβ(1-16), and that Aβ isoforms longer than Aβ(1-16) are reduced, potentially by endothelin converting enzyme, insulin-degrading enzyme, or matrix metalloproteinase-9, enzymes known to cleave at the Aβ(1-17) site.

    SHOW Details   Supporting(3)     Genes/Proteins: (4)

    Experimental Approach: Target validation,   Animal models,   Mechanism - biochemistry and structural biology
    Pathogenic Narrative Tags: Perturbation
    Supporting Evidence
    

    • Cook J, Wildsmith K, Gilberto D, Holahan M, Kinney G, Mathers P, Michener M, Price E, Shearman M, Simon A, Wang J, Wu G, Yarasheski K, Bateman R
      Acute gamma-secretase inhibition of nonhuman primate CNS shifts amyloid precursor protein (APP) metabolism from amyloid-beta production to alternative APP fragments without amyloid-beta rebound.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2010 May 12;30(19):6743-50
    • Yan P, Hu X, Song H, Yin K, Bateman R, Cirrito J, Xiao Q, Hsu F, Turk J, Xu J, Hsu C, Holtzman D, Lee J
      Matrix metalloproteinase-9 degrades amyloid-beta fibrils in vitro and compact plaques in situ.
      The Journal of biological chemistry. 2006 Aug 25;281(34):24566-74
    • Portelius E, Price E, Brinkmalm G, Stiteler M, Olsson M, Persson R, Westman-Brinkmalm A, Zetterberg H, Simon A, Blennow K
      A novel pathway for amyloid precursor protein processing.
      Neurobiology of aging. 2009 Jul 13;

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
    • Protein: Insulin-degrading enzyme [Homo sapiens]
    • Protein: Matrix metalloproteinase-9 [Homo sapiens]
  • The in vivo Aβ stable-isotope-labeling kinetics (SILK) study method involves 13C6 Leucine intravenously administered to rhesus monkeys for 12 h; CSF is collected from the cisterna magna port during and after administration and the incorporation of the label into Aβ is quantitated by immunoprecipitation paired with LC-MS, and the results are used to calculate production and clearance rates.

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

    Experimental Approach: Target validation,   Animal models,   Mechanism - biochemistry and structural biology,  
    Pathogenic Narrative Tags: Initial condition
    Supporting Evidence
    

    • Bateman R, Munsell L, Morris J, Swarm R, Yarasheski K, Holtzman D
      Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo.
      Nature medicine. 2006 Jul;12(7):856-61
    • Bateman R, Munsell L, Chen X, Holtzman D, Yarasheski K
      Stable isotope labeling tandem mass spectrometry (SILT) to quantify protein production and clearance rates.
      Journal of the American Society for Mass Spectrometry. 2007 Jun;18(6):997-1006

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
• Supporting:
  • Single oral administration of two doses of the CNS-penetrant γ-secretase inhibitor (GSI), MK-0752 in healthy male CMP rhesus monkeys demonstrate a dose-related reduction of Aβ40 levels in plasma and CSF Aβ40 and Aβ42 followed by Aβ rebound above baseline in plasma but not in CSF.

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

    Experimental Approach: Mechanism - biochemistry and structural biology,   Target validation,   Animal models
    Pathogenic Narrative Tags: Perturbation
    Supporting Evidence
    

    • Cook J, Wildsmith K, Gilberto D, Holahan M, Kinney G, Mathers P, Michener M, Price E, Shearman M, Simon A, Wang J, Wu G, Yarasheski K, Bateman R
      Acute gamma-secretase inhibition of nonhuman primate CNS shifts amyloid precursor protein (APP) metabolism from amyloid-beta production to alternative APP fragments without amyloid-beta rebound.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2010 May 12;30(19):6743-50

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
  • In rhesus monkeys treated with a high dose of γ-secretase inhibitor (GSI) MK-0752 (240 mg/kg), levels of Aβ(1-14), Aβ(1-15), and Aβ(1-16) increased over vehicle levels, while levels of Aβ(1-17) decreased and these changes occurred concomitantly with an expected reduction in plasma Aβ40 and CSF Aβ40 and Aβ42, followed by peripheral but not central Aβ rebound effects.

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

    Experimental Approach: Target validation,   Mechanism - biochemistry and structural biology,   Animal models
    Pathogenic Narrative Tags: Perturbation
    Supporting Evidence
    

    • Cook J, Wildsmith K, Gilberto D, Holahan M, Kinney G, Mathers P, Michener M, Price E, Shearman M, Simon A, Wang J, Wu G, Yarasheski K, Bateman R
      Acute gamma-secretase inhibition of nonhuman primate CNS shifts amyloid precursor protein (APP) metabolism from amyloid-beta production to alternative APP fragments without amyloid-beta rebound.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2010 May 12;30(19):6743-50

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
  • The GSI MK-0752 reduction of CSF Aβ without a subsequent rebound suggests that in the absence of γ-secretase, the combined proteolytic cleavage of the Aβ precursor by β-secretase and α-secretase generates Aβ(1-14), Aβ(1-15), and Aβ(1-16), and that Aβ isoforms longer than Aβ(1-16) are reduced, potentially by endothelin converting enzyme, insulin-degrading enzyme, or matrix metalloproteinase-9, enzymes known to cleave at the Aβ(1-17) site.

    SHOW Details   Supporting(3)     Genes/Proteins: (4)

    Experimental Approach: Target validation,   Animal models,   Mechanism - biochemistry and structural biology
    Pathogenic Narrative Tags: Perturbation
    Supporting Evidence
    

    • Cook J, Wildsmith K, Gilberto D, Holahan M, Kinney G, Mathers P, Michener M, Price E, Shearman M, Simon A, Wang J, Wu G, Yarasheski K, Bateman R
      Acute gamma-secretase inhibition of nonhuman primate CNS shifts amyloid precursor protein (APP) metabolism from amyloid-beta production to alternative APP fragments without amyloid-beta rebound.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2010 May 12;30(19):6743-50
    • Yan P, Hu X, Song H, Yin K, Bateman R, Cirrito J, Xiao Q, Hsu F, Turk J, Xu J, Hsu C, Holtzman D, Lee J
      Matrix metalloproteinase-9 degrades amyloid-beta fibrils in vitro and compact plaques in situ.
      The Journal of biological chemistry. 2006 Aug 25;281(34):24566-74
    • Portelius E, Price E, Brinkmalm G, Stiteler M, Olsson M, Persson R, Westman-Brinkmalm A, Zetterberg H, Simon A, Blennow K
      A novel pathway for amyloid precursor protein processing.
      Neurobiology of aging. 2009 Jul 13;

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
    • Protein: Insulin-degrading enzyme [Homo sapiens]
    • Protein: Matrix metalloproteinase-9 [Homo sapiens]
• Created On: Fri, May 28 15:04:06 EDT 2010
• Last Modified On: Fri May 28 15:04:06 EDT 2010