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• Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum?
• Citation:
  Klein W, Krafft G, Finch C
  

  Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum?

  Trends in neurosciences. 2001 Apr;24(4):219-24
  [PubMed] [Alzforum]
• Supporting:
  • Aβ oligomers are undetected in typical pathology assays, and thus constitute missing links in the pathogenic cascade.

    SHOW Details   Supporting(1) 

    Experimental Approach:
    Pathogenic Narrative Tags:
    Supporting Evidence
    

    • Klein W, Krafft G, Finch C
      Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum?
      Trends in neurosciences. 2001 Apr;24(4):219-24
  • Oligomeric Aβ intermediate assemblies are potent neurotoxins.

    SHOW Details   Supporting(1)   Consistent(1) 

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

    • Klein W, Krafft G, Finch C
      Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum?
      Trends in neurosciences. 2001 Apr;24(4):219-24

    Consistent statements
    

    • Several lines of evidence indicate that smaller Aβ oligomers, rather than full-fledged fibrils, may be the primary neurotoxic form. Tycko R 
  • Aβ oligomers from human AD brain demonstrate a high capacity to attach to neurons at small clusters of surface binding sites.

    SHOW Details   Supporting(5)   Consistent(1) 

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

    • Lin H, Bhatia R, Lal R
      Amyloid beta protein forms ion channels: implications for Alzheimer's disease pathophysiology.
      The FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2001 Nov;15(13):2433-44
    • Gong Y, Chang L, Viola K, Lacor P, Lambert M, Finch C, Krafft G, Klein W
      Alzheimer's disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss.
      Proceedings of the National Academy of Sciences of the United States of America. 2003 Sep 2;100(18):10417-22
    • Lambert M, Barlow A, Chromy B, Edwards C, Freed R, Liosatos M, Morgan T, Rozovsky I, Trommer B, Viola K, Wals P, Zhang C, Finch C, Krafft G, Klein W
      Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins.
      Proceedings of the National Academy of Sciences of the United States of America. 1998 May 26;95(11):6448-53
    • Kourie J, Culverson A, Farrelly P, Henry C, Laohachai K
      Heterogeneous amyloid-formed ion channels as a common cytotoxic mechanism: implications for therapeutic strategies against amyloidosis.
      Cell biochemistry and biophysics. 2002;36(2-3):191-207
    • Klein W, Krafft G, Finch C
      Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum?
      Trends in neurosciences. 2001 Apr;24(4):219-24

    Consistent statements
    

    • ADDL binding sites comprise particular domains of cell surface proteins and that these domains, when solubilized by trypsin, provide neuroprotective, ADDL-neutralizing activity. Lambert M  Barlow A  Chromy B  Edwards C  Freed R  Liosatos M  Morgan T  Rozovsky I  Trommer B  Viola K  Wals P  Zhang C  Finch C  Krafft G  Klein W 
  • Soluble Aβ assemblies disrupt memory.

    SHOW Details   Supporting(4)   Consistent(5)   Alternative to: (2)

    Description: The authors hypothesize the existence of soluble Aβ assemblies that disrupt memory. This Aβ satisfied two criteria: that its appearance should coincide with early memory loss and then remain stable in middle-aged mice.
    Experimental Approach: Mechanism - biochemistry and structural biology,   Biomarkers,   Animal models,   Neuropsychology/Behavior,   Pathophysiology,  
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Ashe K
      Learning and memory in transgenic mice modeling Alzheimer's disease.
      Learning & memory (Cold Spring Harbor, N.Y.). 2001;8(6):301-8
    • Hsia A, Masliah E, McConlogue L, Yu G, Tatsuno G, Hu K, Kholodenko D, Malenka R, Nicoll R, Mucke L
      Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models.
      Proceedings of the National Academy of Sciences of the United States of America. 1999 Mar 16;96(6):3228-33
    • Westerman M, Cooper-Blacketer D, Mariash A, Kotilinek L, Kawarabayashi T, Younkin L, Carlson G, Younkin S, Ashe K
      The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer's disease.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2002 Mar 1;22(5):1858-67
    • Klein W, Krafft G, Finch C
      Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum?
      Trends in neurosciences. 2001 Apr;24(4):219-24

    Consistent statements
    

    • The degree of dementia in AD correlates with concentration of soluble Aβ. Hardy J  Selkoe D 
    • Aβ oligomers inhibit long term potentiation in the hippocampus. Hardy J  Selkoe D 
    • Soluble oligomers of Aβ, not monomeric Aβ or insoluble fibrillar Aβ, may be responsible for synaptic dysfunction in brains of AD patients and animal models of AD. Hardy J  Selkoe D 
    • Soluble Aβ oligomers, not monomers or fibrils, interfere with synaptic plasticity. Hardy J  Selkoe D 
    • The presence of elevated concentration of soluble amyloid beta (Aβ) protein in entorhinal cortex or superior frontal gyrus is well correlated with the prediction of AD. Morse T  Mutalik P  Cheung K  Miller P  Shepherd G 

    Alternative statements
    

    • The intramembranous APP C-terminal fragments may be toxic in situ. Marchesi V 
    • Persistence of Aβ dimers in the membrane could have significant impact on health of neurons. Marchesi V 
  • Transgenic mice demonstrate neurologic deficits prior to appearance of amyloid deposits.

    SHOW Details   Supporting(2)   Consistent(3)   Alternative to: (1)

    Experimental Approach: Pathophysiology,   Animal models
    Pathogenic Narrative Tags: Pathogenic event
    Supporting Evidence
    

    • Mucke L, Masliah E, Yu G, Mallory M, Rockenstein E, Tatsuno G, Hu K, Kholodenko D, Johnson-Wood K, McConlogue L
      High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2000 Jun 1;20(11):4050-8
    • Klein W, Krafft G, Finch C
      Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum?
      Trends in neurosciences. 2001 Apr;24(4):219-24

    Consistent statements
    

    • Amyloid is the consequence, not the cause, of AD.
      Smith M, Perry G, Castellani R, Lee H Wed, Feb 10 2010 17:25:40 EST SHOW Details 
      Rather than amyloid being responsible for causing disease, we suspect that Alzheimer Disease is responsible for causing amyloid. In fact, amyloid may even be a protective response. As such, removing amyloid would be predicted to either have no effect or a detrimental effect on AD progression.
      

      • Joseph et al., 2001
      • Smith et al., 2002
      • Lee et al., 2004
      • Smith et al., 2002
      • Perry et al., 2000
      • Atwood et al., 2002
      • Lee et al., 2006
    • Several lines of evidence indicate that smaller Aβ oligomers, rather than full-fledged fibrils, may be the primary neurotoxic form. Tycko R 
    • Young APP transgenic mice undergo synaptic, electrophysiological and behavioral changes before amyloid plaque deposition. Walsh D  Klyubin I  Fadeeva J  Cullen W  Anwyl R  Wolfe M  Rowan M  Selkoe D 

    Alternative statements
    

    • Transgenic mice that demonstrate progressive Aβ deposition often do not suffer neuronal loss. Hardy J  Selkoe D 
  • Memory failure in APP transgenic mice is reversed by anti-Aβ; antibodies, and the memory recovery is rapid, occurring within 24 h of a single injection of antibody, without reducing amyloid plaque load.

    SHOW Details   Supporting(4)   Alternative to: (1)

    Experimental Approach: Animal models,   Neuropsychology/Behavior,   Target validation
    Pathogenic Narrative Tags: Pathogenic event
    Supporting Evidence
    

    • Dodart J, Bales K, Gannon K, Greene S, DeMattos R, Mathis C, DeLong C, Wu S, Wu X, Holtzman D, Paul S
      Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model.
      Nature neuroscience. 2002 May;5(5):452-7
    • Klein W, Krafft G, Finch C
      Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum?
      Trends in neurosciences. 2001 Apr;24(4):219-24
    • Lambert M, Barlow A, Chromy B, Edwards C, Freed R, Liosatos M, Morgan T, Rozovsky I, Trommer B, Viola K, Wals P, Zhang C, Finch C, Krafft G, Klein W
      Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins.
      Proceedings of the National Academy of Sciences of the United States of America. 1998 May 26;95(11):6448-53
    • Gong Y, Chang L, Viola K, Lacor P, Lambert M, Finch C, Krafft G, Klein W
      Alzheimer's disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss.
      Proceedings of the National Academy of Sciences of the United States of America. 2003 Sep 2;100(18):10417-22

    Alternative statements
    

    • Enhanced peripheral clearance and (or) sequestration of Aβ in brain might underlie the rapid reversal of memory impairment that followed the antibody treatment. Dodart J  Bales K  Gannon K  Greene S  DeMattos R  Mathis C  DeLong C  Wu S  Wu X  Holtzman D  Paul S 
  • AD brain extracts incubated with cultured rat hippocampal neurons and stained with oligomer-selective antibodies demonstrate abundant, punctate staining pattern of ADDLs along neurites, resembling synaptic terminals.

    SHOW Details   Supporting(3) 

    Experimental Approach: Mechanism - biochemistry and structural biology,   Mechanism - physiological systems
    Pathogenic Narrative Tags: Pathogenic event
    Supporting Evidence
    

    • Lambert M, Barlow A, Chromy B, Edwards C, Freed R, Liosatos M, Morgan T, Rozovsky I, Trommer B, Viola K, Wals P, Zhang C, Finch C, Krafft G, Klein W
      Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins.
      Proceedings of the National Academy of Sciences of the United States of America. 1998 May 26;95(11):6448-53
    • Gong Y, Chang L, Viola K, Lacor P, Lambert M, Finch C, Krafft G, Klein W
      Alzheimer's disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss.
      Proceedings of the National Academy of Sciences of the United States of America. 2003 Sep 2;100(18):10417-22
    • Klein W, Krafft G, Finch C
      Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum?
      Trends in neurosciences. 2001 Apr;24(4):219-24
  • The amyloid cascade hypothesis has been modified to include soluble Aβ oligomers

    SHOW Details   Supporting(3) 

    Experimental Approach: Mechanism - biochemistry and structural biology,   Pathophysiology,  
    Pathogenic Narrative Tags: Pathogenic event
    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
    • Gong Y, Chang L, Viola K, Lacor P, Lambert M, Finch C, Krafft G, Klein W
      Alzheimer's disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss.
      Proceedings of the National Academy of Sciences of the United States of America. 2003 Sep 2;100(18):10417-22
    • Klein W, Krafft G, Finch C
      Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum?
      Trends in neurosciences. 2001 Apr;24(4):219-24
  • The pathogenic role of amyloid fibrils has not been universally accepted because of a poor correlation between neurological deficits and amyloid plaque burden, in human AD brain as well as transgenic mouse models.

    SHOW Details   Supporting(3)   Consistent(4)   Inconsistent(1)   Alternative to: (3)

    Experimental Approach: Neuropsychology/Behavior,   Animal models,   Pathophysiology
    Pathogenic Narrative Tags: Pathogenic event
    Supporting Evidence
    

    • Klein W, Krafft G, Finch C
      Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum?
      Trends in neurosciences. 2001 Apr;24(4):219-24
    • Mucke L, Masliah E, Yu G, Mallory M, Rockenstein E, Tatsuno G, Hu K, Kholodenko D, Johnson-Wood K, McConlogue L
      High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2000 Jun 1;20(11):4050-8
    • Gong Y, Chang L, Viola K, Lacor P, Lambert M, Finch C, Krafft G, Klein W
      Alzheimer's disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss.
      Proceedings of the National Academy of Sciences of the United States of America. 2003 Sep 2;100(18):10417-22

    Consistent statements
    

    • Differential activation of the innate immune system by different protein aggregates and variable clearance of the aggregates following immune activation probably contribute to the imperfect correlations between the amounts and regional distribution of protein aggregates with clinical and neuropathological phenotypes. Golde T  Miller V 
    • Neither plaques nor tangles correlated with mental status. Neither ChAT nor somatostatin assays correlated with mental status. Terry R  Masliah E  Salmon D  Butters N  DeTeresa R  Hill R  Hansen L  Katzman R 
    • Synaptic loss may well occur before disappearance of the neuronal perikaryon, and the loss of synapses in neocortex causes a functionally important disconnection between regions of the neocortex involved in cognition.
    • In extensive studies, no clear correlation between deposited forms of Aβ (such as plaques) and memory impairment in AD patients has been demonstrated. Dodart J  Bales K  Gannon K  Greene S  DeMattos R  Mathis C  DeLong C  Wu S  Wu X  Holtzman D  Paul S 

    Inconsistent statements
    

    • The earliest association between cerebral plaques and tangles with presenile dementia, was first suggested by Alzheimer. Terry R  Masliah E  Salmon D  Butters N  DeTeresa R  Hill R  Hansen L  Katzman R 

    Alternative statements
    

    • The relationship between soluble and insoluble brain Aβ concentrations and memory impairment in transgenic mice is task specific and complex. Dodart J  Bales K  Gannon K  Greene S  DeMattos R  Mathis C  DeLong C  Wu S  Wu X  Holtzman D  Paul S 
    • The degree of dementia in AD correlates with concentration of soluble Aβ. Hardy J  Selkoe D 
    • The brains of many cognitively normal aged individuals show abundant Aβ containing senile plaques but no clinical signs of Alzheimer disease. Aliev G 
  • Aβ oligomers may be key effectors of neurotoxicity.

    SHOW Details   Supporting(1)   Consistent(1) 

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

    • Klein W, Krafft G, Finch C
      Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum?
      Trends in neurosciences. 2001 Apr;24(4):219-24

    Consistent statements
    

    • Several lines of evidence indicate that smaller Aβ oligomers, rather than full-fledged fibrils, may be the primary neurotoxic form. Tycko R 
• Created On: Wed, Apr 23 08:59:48 EDT 2008
• Last Modified On: Wed Apr 23 08:59:48 EDT 2008