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• Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.
• Citation:
  De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F
  

  Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.

  Nature. 1998 Jan 22;391(6665):387-90
  [PubMed] [Alzforum]
• Supporting:
  • The explicit prediction that causes of Alzheimer Disease would relate to amyloid production and clearance was fulfilled when presenilins were cloned and shown to directly relate to amyloid production, with presenilin mutations increasing the production of Aβ42 in people with mutations and in cells and transgenic mice.

    SHOW Details   Supporting(8)     Genes/Proteins: (3)

    Experimental Approach: Mechanism - biochemistry and structural biology,   Genetics,   Mechanism - molecular and cell,   Animal models
    Pathogenic Narrative Tags: Initial condition
    Supporting Evidence
    

    • Rogaev E, Sherrington R, Rogaeva E, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T
      Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene.
      Nature. 1995 Aug 31;376(6543):775-8
    • De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F
      Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.
      Nature. 1998 Jan 22;391(6665):387-90
    • Wolfe M, Xia W, Ostaszewski B, Diehl T, Kimberly W, Selkoe D
      Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity.
      Nature. 1999 Apr 8;398(6727):513-7
    • Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird T, Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E, Poorkaj P, Schellenberg G, Tanzi R, Wasco W, Lannfelt L, Selkoe D, Younkin S
      Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease.
      Nature medicine. 1996 Aug;2(8):864-70
    • Levy-Lahad E, Wasco W, Poorkaj P, Romano D, Oshima J, Pettingell W, Yu C, Jondro P, Schmidt S, Wang K
      Candidate gene for the chromosome 1 familial Alzheimer's disease locus.
      Science (New York, N.Y.). 1995 Aug 18;269(5226):973-7
    • Duff K, Eckman C, Zehr C, Yu X, Prada C, Perez-tur J, Hutton M, Buee L, Harigaya Y, Yager D, Morgan D, Gordon M, Holcomb L, Refolo L, Zenk B, Hardy J, Younkin S
      Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1.
      Nature. 1996 Oct 24;383(6602):710-3
    • Sherrington R, Rogaev E, Liang Y, Rogaeva E, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K
      Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease.
      Nature. 1995 Jun 29;375(6534):754-60
    • Borchelt D, Thinakaran G, Eckman C, Lee M, Davenport F, Ratovitsky T, Prada C, Kim G, Seekins S, Yager D, Slunt H, Wang R, Seeger M, Levey A, Gandy S, Copeland N, Jenkins N, Price D, Younkin S, Sisodia S
      Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo.
      Neuron. 1996 Nov;17(5):1005-13

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Gene: PSEN1 presenilin 1 [Homo sapiens]
    • Gene: PSEN2 presenilin 2 (Alzheimer disease 4) [Homo sapiens]
  • γ-secretase activity is responsible for the final cleavage of the amyloid precursor protein (APP), causing release of the Aβ peptide, cleaves Notch, N-Cadherin, and other important signaling molecules and is mediated by a multiprotein complex consisting of Presenilin (PS), Aph1, Pen2, and Nicastrin (NCT).

    SHOW Details   Supporting(1)   Consistent(1)     Genes/Proteins: (11)

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

    • De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F
      Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.
      Nature. 1998 Jan 22;391(6665):387-90

    Consistent statements
    

    • Cadherins seem to undergo γ-secretase-dependent cleavages, although the physiological significance of this cleavage is unclear. Shen J  Kelleher R 

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
    • Protein: Cadherin-2 [Homo sapiens]
    • Protein: Presenilin-1 [Homo sapiens]
    • Protein: Beta-amyloid protein 40 [Homo sapiens]
    • Protein: Neurogenic locus notch homolog protein 1 [Homo sapiens]
    • Protein: Nicastrin [Homo sapiens]
    • Protein: Gamma-secretase subunit APH-1B [Homo sapiens]
    • Protein: Gamma-secretase subunit PEN-2 [Homo sapiens]
    • Protein: Presenilin-2 [Homo sapiens]
    • Protein: Amyloid beta A4 protein [Homo sapiens]
    • Protein: Gamma-secretase subunit APH-1A [Homo sapiens]
  • Two opposing ideas exist regarding the role of PS clinical mutations in APP processing: arguing for gain of function, all PS mutations enhance the Aβ42:40 ratio; but in support of loss of function, a total loss of Ps results in a total loss of Aβ production.

    SHOW Details   Supporting(2)   Consistent(2)   Alternative to: (3)

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

    • De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F
      Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.
      Nature. 1998 Jan 22;391(6665):387-90
    • Herreman A, Serneels L, Annaert W, Collen D, Schoonjans L, De Strooper B
      Total inactivation of gamma-secretase activity in presenilin-deficient embryonic stem cells.
      Nature cell biology. 2000 Jul;2(7):461-2

    Consistent statements
    

    • Although initial investigations of FAD-linked PS mutations in mammalian systems focused on enhancement of Aβ42 production, it has now become clear that a large number of pathogenic mutations cause impairments in other PS activities. Shen J  Kelleher R 
    • Of the major cleavages of APP mediated by γ-secretase, PS mutations typically increase the production of Aβ42 (and Aβ43), but can impair the normally predominant γ-cleavage following Aβ residue 40 and the more distal ‘‘ε-cleavage’’ following residue 49, resulting in significantly reduced generation of Aβ40 and AICD, respectively. Shen J  Kelleher R 

    Alternative statements
    

    • FAD-linked PS mutations are likely to be genetically antimorphic, causing an intrinsic loss of function as well as a gain of negative function, thereby bringing about an overall loss of PS activity. Shen J  Kelleher R 
    • The diffuse distribution of PS mutations is most compatible with a loss of function. Shen J  Kelleher R 
    • Increased levels of Aβ may cause AD by interfering with PS function and/or expression, resulting in a loss of PS-dependent activities. Shen J  Kelleher R 
  • Presenilins form the catalytic core of the gamma-secretase complex.

    SHOW Details   Supporting(2) 

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

    • De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F
      Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.
      Nature. 1998 Jan 22;391(6665):387-90
    • Wolfe M, Xia W, Ostaszewski B, Diehl T, Kimberly W, Selkoe D
      Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity.
      Nature. 1999 Apr 8;398(6727):513-7
  • PS1 and PS2 alter APP metabolism through a direct effect on the γ-secretase protease.

    SHOW Details   Supporting(5)     Genes/Proteins: (4)

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

    • Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Seubert P, Davis A, Kholodenko D, Motter R, Sherrington R, Perry B, Yao H, Strome R, Lieberburg I, Rommens J, Kim S, Schenk D, Fraser P, St George Hyslop P, Selkoe D
      Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice.
      Nature medicine. 1997 Jan;3(1):67-72
    • Borchelt D, Thinakaran G, Eckman C, Lee M, Davenport F, Ratovitsky T, Prada C, Kim G, Seekins S, Yager D, Slunt H, Wang R, Seeger M, Levey A, Gandy S, Copeland N, Jenkins N, Price D, Younkin S, Sisodia S
      Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo.
      Neuron. 1996 Nov;17(5):1005-13
    • Wolfe M, Xia W, Ostaszewski B, Diehl T, Kimberly W, Selkoe D
      Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity.
      Nature. 1999 Apr 8;398(6727):513-7
    • De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F
      Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.
      Nature. 1998 Jan 22;391(6665):387-90
    • Duff K, Eckman C, Zehr C, Yu X, Prada C, Perez-tur J, Hutton M, Buee L, Harigaya Y, Yager D, Morgan D, Gordon M, Holcomb L, Refolo L, Zenk B, Hardy J, Younkin S
      Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1.
      Nature. 1996 Oct 24;383(6602):710-3

    Genes/Proteins
    

    • Protein: Presenilin-1 [Homo sapiens]
    • Gene: PSEN1 presenilin 1 [Homo sapiens]
    • Gene: PSEN2 presenilin 2 (Alzheimer disease 4) [Homo sapiens]
    • Protein: Presenilin-2 [Homo sapiens]
  • γ-secretase cleaves many substrates including APP, Notch, and syndecan 3 in the hydrophobic environment of the membrane.

    SHOW Details   Supporting(5)   Consistent(2)     Genes/Proteins: (1)

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

    • De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F
      Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.
      Nature. 1998 Jan 22;391(6665):387-90
    • De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm J, Schroeter E, Schrijvers V, Wolfe M, Ray W, Goate A, Kopan R
      A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.
      Nature. 1999 Apr 8;398(6727):518-22
    • Kopan R, Ilagan M
      Gamma-secretase: proteasome of the membrane?
      Nature reviews. Molecular cell biology. 2004 Jun;5(6):499-504
    • De Strooper B
      Aph-1, Pen-2, and Nicastrin with Presenilin generate an active gamma-Secretase complex.
      Neuron. 2003 Apr 10;38(1):9-12
    • Schulz J, Annaert W, Vandekerckhove J, Zimmermann P, De Strooper B, David G
      Syndecan 3 intramembrane proteolysis is presenilin/gamma-secretase-dependent and modulates cytosolic signaling.
      The Journal of biological chemistry. 2003 Dec 5;278(49):48651-7

    Consistent statements
    

    • Cleavage of APP by alpha-secretase or by beta-cleavage alone may leave APP cleavage products within the membrane. Marchesi V 
    • Aβ peptides exist in neuronal membrane fragments, and the simplest interpretation of this finding is that APP dimers are cleaved by the secretases as dimers. Marchesi V 

    Genes/Proteins
    

    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • The identity of the γ-secretase has been proposed to be a complex of enzymes composed of presenilin-1 or -2, (PS1 and PS2), nicastrin, aph-1 and pen-2.

    SHOW Details   Supporting(4) 

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

    • Levitan D, Lee J, Song L, Manning R, Wong G, Parker E, Zhang L
      PS1 N- and C-terminal fragments form a complex that functions in APP processing and Notch signaling.
      Proceedings of the National Academy of Sciences of the United States of America. 2001 Oct 9;98(21):12186-90
    • Steiner H, Winkler E, Edbauer D, Prokop S, Basset G, Yamasaki A, Kostka M, Haass C
      PEN-2 is an integral component of the gamma-secretase complex required for coordinated expression of presenilin and nicastrin.
      The Journal of biological chemistry. 2002 Oct 18;277(42):39062-5
    • Francis R, McGrath G, Zhang J, Ruddy D, Sym M, Apfeld J, Nicoll M, Maxwell M, Hai B, Ellis M, Parks A, Xu W, Li J, Gurney M, Myers R, Himes C, Hiebsch R, Ruble C, Nye J, Curtis D
      aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation.
      Developmental cell. 2002 Jul;3(1):85-97
    • De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F
      Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.
      Nature. 1998 Jan 22;391(6665):387-90
  • Four different well characterized substrates of γ-secretase include syndecan 3, N-cadherin, Notch deltaE and APP.

    SHOW Details   Supporting(4)   Consistent(2)     Genes/Proteins: (1)

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

    • De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm J, Schroeter E, Schrijvers V, Wolfe M, Ray W, Goate A, Kopan R
      A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.
      Nature. 1999 Apr 8;398(6727):518-22
    • Schulz J, Annaert W, Vandekerckhove J, Zimmermann P, De Strooper B, David G
      Syndecan 3 intramembrane proteolysis is presenilin/gamma-secretase-dependent and modulates cytosolic signaling.
      The Journal of biological chemistry. 2003 Dec 5;278(49):48651-7
    • Marambaud P, Wen P, Dutt A, Shioi J, Takashima A, Siman R, Robakis N
      A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations.
      Cell. 2003 Sep 5;114(5):635-45
    • De Strooper B, Saftig P, Craessaerts K, Vanderstichele H, Guhde G, Annaert W, Von Figura K, Van Leuven F
      Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein.
      Nature. 1998 Jan 22;391(6665):387-90

    Consistent statements
    

    • Cadherins seem to undergo γ-secretase-dependent cleavages, although the physiological significance of this cleavage is unclear. Shen J  Kelleher R 
    • PS1 and PS2 proteins are essential components of γ-secretase , a multisubunit protease complex that catalyzes the intramembranous cleavage of a number of type I transmembrane proteins, including Notch, APP, and cadherins. Shen J  Kelleher R 

    Genes/Proteins
    

    • Protein: Amyloid beta A4 protein [Homo sapiens]
• Created On: Wed, Apr 23 06:30:16 EDT 2008
• Last Modified On: Wed Apr 23 06:30:16 EDT 2008