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• The channel hypothesis of Alzheimer's disease: current status.
• Citation:
  Kagan B, Hirakura Y, Azimov R, Azimova R, Lin M
  

  The channel hypothesis of Alzheimer's disease: current status.

  Peptides. 2002 Jul;23(7):1311-5
  [PubMed] [Alzforum]
• Supporting:
  • The "channel hypothesis" proposes that extracellular Aβ can re-insert into the membrane, associate together and create channels that allow lethal levels of calcium into the cell.

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

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

    • Kagan B, Hirakura Y, Azimov R, Azimova R, Lin M
      The channel hypothesis of Alzheimer's disease: current status.
      Peptides. 2002 Jul;23(7):1311-5
    • Kayed R, Sokolov Y, Edmonds B, McIntire T, Milton S, Hall J, Glabe C
      Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases.
      The Journal of biological chemistry. 2004 Nov 5;279(45):46363-6

    Consistent statements
    

    • Insertion of Aβ channels into the plasma membranes could slowly cause changes in neuronal membrane potentials leading to alterations in neuronal firing. Smith I  Green K  LaFerla F 
    • Aβ has been shown to spontaneously form voltage-dependent cation selective channels in lipid bilayers that can conduct calcium. Smith I  Green K  LaFerla F 
    • Aβ could form novel channels in the plasma membrane and subcellular organelle membranes, thereby causing an unregulated influx of calcium (or other ions) that may contribute to neurodegeneration. Smith I  Green K  LaFerla F 
    • Transgenic mice expressing different mutant PS1 in the absence of human APP mutations, do not develop amyloid-β plaques and also do not exhibit any appreciable calcium overload compared to their respective controls. These data suggest that calcium overload requires mutant APP processing and amyloid-β aggregates. Kuchibhotla K  Goldman S  Lattarulo C  Wu H  Hyman B  Bacskai B 

    Alternative statements
    

    • Aβ can alter the activity of a number calcium conducting ion channels such as voltage-gated calcium channels, NMDA receptors and nicotinic receptors. Smith I  Green K  LaFerla F 
    • Formation of Aβ ion channels in the mitochondrial membranes may disrupt mitochondrial membrane potential impairing energy production and leading to apoptosis. Smith I  Green K  LaFerla F 

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
  • Some Aβ peptides may never leave the membrane.

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

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

    • Kayed R, Sokolov Y, Edmonds B, McIntire T, Milton S, Hall J, Glabe C
      Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases.
      The Journal of biological chemistry. 2004 Nov 5;279(45):46363-6
    • Kagan B, Hirakura Y, Azimov R, Azimova R, Lin M
      The channel hypothesis of Alzheimer's disease: current status.
      Peptides. 2002 Jul;23(7):1311-5

    Consistent statements
    

    • Marchesi's hypothesis could illuminate why Aβ42 prefers to be retained in cells upon exocytosis of more soluble Aβ40 peptides. Gouras G 

    Inconsistent statements
    

    • The processing of a large and growing number of substrates by γ-secretase has led to the hypothesis that γ-secretase is conserved and ubiquitous because it efficiently removes single-transmembrane proteins from the bilayer. Selkoe D 
    • Robust release of Aβ monomer following γ-secretase processing of endogenous APP has also been shown in primary human neurons and healthy cultured cells expressing APP. Selkoe D 

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
• Created On: Wed, Apr 23 07:03:02 EDT 2008
• Last Modified On: Wed Apr 23 07:03:02 EDT 2008