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• Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
• Citation:
  Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
  

  Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.

  Nature. 2002 Apr 4;416(6880):535-9
  [PubMed] [Alzforum]
• Source For Statements:
  • Transgenic mice overexpressing human APP have demonstrated failure of LTP maintenance, but such studies have not identified the biochemically defined assembly forms responsible for LTP failure.

    SHOW Details   Supporting(6)     Genes/Proteins: (2)

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

    • Chapman P, White G, Jones M, Cooper-Blacketer D, Marshall V, Irizarry M, Younkin L, Good M, Bliss T, Hyman B, Younkin S, Hsiao K
      Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice.
      Nature neuroscience. 1999 Mar;2(3):271-6
    • Moechars D, Dewachter I, Lorent K, Reversé D, Baekelandt V, Naidu A, Tesseur I, Spittaels K, Haute C, Checler F, Godaux E, Cordell B, Van Leuven F
      Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain.
      The Journal of biological chemistry. 1999 Mar 5;274(10):6483-92
    • 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
    • Larson J, Lynch G, Games D, Seubert P
      Alterations in synaptic transmission and long-term potentiation in hippocampal slices from young and aged PDAPP mice.
      Brain research. 1999 Sep 4;840(1-2):23-35
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Fitzjohn S, Morton R, Kuenzi F, Rosahl T, Shearman M, Lewis H, Smith D, Reynolds D, Davies C, Collingridge G, Seabrook G
      Age-related impairment of synaptic transmission but normal long-term potentiation in transgenic mice that overexpress the human APP695SWE mutant form of amyloid precursor protein.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2001 Jul 1;21(13):4691-8

    Genes/Proteins
    

    • Gene: APP amyloid beta (A4) precursor protein [Homo sapiens]
    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • LTP is a measure of synaptic plasticity that is disrupted by synthetic Aβ.

    SHOW Details   Supporting(2)   Consistent(2) 

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Kim J, Anwyl R, Suh Y, Djamgoz M, Rowan M
      Use-dependent effects of amyloidogenic fragments of (beta)-amyloid precursor protein on synaptic plasticity in rat hippocampus in vivo.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2001 Feb 15;21(4):1327-33

    Consistent statements
    

    • Aβ oligomers inhibit long term potentiation in the hippocampus. Hardy J  Selkoe D 
    • ADDLs block the reversal of LTD and formation of LTP, and may lead to synapse destabilization. Gong Y  Chang L  Viola K  Lacor P  Lambert M  Finch C  Krafft G  Klein W 
  • Soluble, stable Aβ oligomers can be produced by cultured cells.

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

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Walsh D, Tseng B, Rydel R, Podlisny M, Selkoe D
      The oligomerization of amyloid beta-protein begins intracellularly in cells derived from human brain.
      Biochemistry. 2000 Sep 5;39(35):10831-9
    • Morishima-Kawashima M, Ihara Y
      The presence of amyloid beta-protein in the detergent-insoluble membrane compartment of human neuroblastoma cells.
      Biochemistry. 1998 Nov 3;37(44):15247-53
    • Podlisny M, Ostaszewski B, Squazzo S, Koo E, Rydell R, Teplow D, Selkoe D
      Aggregation of secreted amyloid beta-protein into sodium dodecyl sulfate-stable oligomers in cell culture.
      The Journal of biological chemistry. 1995 Apr 21;270(16):9564-70

    Genes/Proteins
    

    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • Conditioned media from V717F APP751 transfected cells completely blocked LTP whereas untransfected cell conditioned media had no effect.

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

    Experimental Approach: Pathophysiology,   Mechanism - molecular and cell,   Genetics,   Mechanism - physiological systems,  
    Pathogenic Narrative Tags: Pathogenic event
    Supporting Evidence
    

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Consistent statements
    

    • Previous studies have demonstrated that a soluble non-fibrillar form of Aβ could alter LTP. Walsh D 

    Genes/Proteins
    

    • Gene: APP amyloid beta (A4) precursor protein [Homo sapiens]
    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • Microsomes isolated from cells expressing V717F mutant APP751 contain Aβ monomers and oligomers.

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

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Genes/Proteins
    

    • Gene: APP amyloid beta (A4) precursor protein [Homo sapiens]
    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • Incubation of V717F APP751 transfected cell conditioned media with insulin degrading enzyme selectively degraded and removed monomeric Aβ leaving Aβ oligomers unchanged.

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

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Consistent statements
    

    • IDE is only able to degrade Aβ monomers. Tanzi R  Moir R  Wagner S 

    Genes/Proteins
    

    • Gene: APP amyloid beta (A4) precursor protein [Homo sapiens]
    • Gene: IDE insulin-degrading enzyme [Homo sapiens]
    • Protein: Amyloid beta A4 protein [Homo sapiens]
    • Protein: Insulin-degrading enzyme [Homo sapiens]
  • Conditioned media from V717F APP751 transfected cells did not affect baseline transmission in the absence of high-frequency stimulation.

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

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Consistent statements
    

    • Additional studies have confirmed that conditioned media from V717F APP751 transfected cells does not alter baseline transmission, using mouse hippocampal slice cultures in vitro. Walsh D 

    Genes/Proteins
    

    • Gene: APP amyloid beta (A4) precursor protein [Homo sapiens]
    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • Immunodepletion-induced prevention of LTP blockage was not due to a non-specific effect of R1282 present in the V717F APP751 conditioned media, since R1282 added to untransfected cell conditioned media had no effect on LTP.

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

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Genes/Proteins
    

    • Gene: APP amyloid beta (A4) precursor protein [Homo sapiens]
    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • Fibrillar plaque density correlates weakly with severity of dementia in AD.

    SHOW Details   Supporting(3)   Consistent(4)   Inconsistent(2)   Alternative to: (2)

    Experimental Approach: Pathophysiology,   Mechanism - biochemistry and structural biology,   Neuropsychology/Behavior
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Dickson D, Crystal H, Bevona C, Honer W, Vincent I, Davies P
      Correlations of synaptic and pathological markers with cognition of the elderly.
      Neurobiology of aging. 1995;16(3):285-98; discussion 298-304
    • Terry R, Masliah E, Salmon D, Butters N, DeTeresa R, Hill R, Hansen L, Katzman R
      Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment.
      Annals of neurology. 1991 Oct;30(4):572-80

    Consistent statements
    

    • In transgenic mouse and rat models with Aβ deposition, synaptic changes occur before plaque accumulation, evidence that gives strength to the idea that the soluble nonfibrillary species of Aβ plays a crucial role in AD pathogenesis. Dziewczapolski G  Glogowski C  Masliah E  Heinemann S 
    • 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 
    • A fundamental tenet of the amyloid hypothesis of Alzheimer’s disease is that the deposition of amyloid-beta precedes and induces the neuronal abnormalities that underlie dementia. Meyer-Luehmann M  Spires-Jones T  Prada C  Garcia-Alloza M  de Calignon A  Rozkalne A  Koenigsknecht-Talboo J  Holtzman D  Bacskai B  Hyman B 

    Alternative statements
    

    • The degree of dementia in AD correlates with concentration of soluble Aβ. Hardy J  Selkoe D 
    • The earliest pathological event that occurs in the process of AD is probably the deposition of insoluble forms of Aβ peptide in the brain. Holtzman D 
  • Immunodepletion of Aβ from V717F APP751 conditioned media using R1282 antibody completely prevented the block of LTP.

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

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Genes/Proteins
    

    • Gene: APP amyloid beta (A4) precursor protein [Homo sapiens]
    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • Aβ oligomer amounts are not reduced with previous trypsinization of intact cells, supporting their intracellular origin.

    SHOW Details   Supporting(1) 

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
  • LTP of excitatory synaptic transmission in the CA1 region is induced by high-frequency stimulation.

    SHOW Details   Supporting(1) 

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
  • Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.

    SHOW Details 

    Description: This hypothesis describes the production, secretion and biological effects of oligomeric Aβ on LTP, and suggests that Aβ oligomers are the principal effectors of synaptic dysfunction and loss that characterize Alzheimer Disease. The authors show that Aβ oligomers are formed within intracellular vesicles, secreted from the cell, stay soluble in conditioned media of transfected cells, and most importantly, have a significant effect on inhibiting hippocampal LTP in vivo. Treatment of cells with γ-secretase inhibitors prevents oligomer formation and oligomer-deficient conditioned media has no effect on LTP. The authors suggest that Aβ oligomers can be targeted therapeutically.
    Contained Discourse: 28 Elements
    Experimental Approach:
    Pathogenic Narrative Tags:
    
  • Inhibition of hippocampal LTP in vivo is specifically due to presence of oligomeric Aβ, not monomers or fibrils.

    SHOW Details   Supporting(1)   Consistent(3) 

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Consistent statements
    

    • A specific form of naturally secreted Aβ blocks long-term potentiation in the absence of monomers, protofibrils and fibrils, directly in living, anesthetized rats. Selkoe D 
    • Previous studies have demonstrated that a soluble non-fibrillar form of Aβ could alter LTP. Walsh D 
    • A chemical compound that inhibits the production of Aβ is used to lower the oligomers enough to completely prevent the synaptic interruption, while still leaving appreciable monomer levels (60 percent of normal). Selkoe D 
  • Oligomer-depleted conditioned media did not block hippocampal LTP despite maintenance of significant levels of monomeric Aβ.

    SHOW Details   Supporting(1)   Consistent(2) 

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Consistent statements
    

    • An additional study extends the finding that conditioned media depleted of Aβ monomers blocked LTP, by comparing the effect of size exclusion chromatography (SEC) separated monomer and oligomers, and by demonstrating that the effect can be blocked using mouse hippocampii. Walsh D 
    • A chemical compound that inhibits the production of Aβ is used to lower the oligomers enough to completely prevent the synaptic interruption, while still leaving appreciable monomer levels (60 percent of normal). Selkoe D 
  • Aβ oligomers are composed of Aβ40 and Aβ42.

    SHOW Details   Supporting(2) 

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

    • Podlisny M, Ostaszewski B, Squazzo S, Koo E, Rydell R, Teplow D, Selkoe D
      Aggregation of secreted amyloid beta-protein into sodium dodecyl sulfate-stable oligomers in cell culture.
      The Journal of biological chemistry. 1995 Apr 21;270(16):9564-70
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
  • Aβ-lowering compounds that prevent intra- or extracellular oligomerization would be an attractive therapeutic approach to selectively reduce synaptotoxicity.

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

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Rochet J, Lansbury P
      Amyloid fibrillogenesis: themes and variations.
      Current opinion in structural biology. 2000 Feb;10(1):60-8
    • Chiti F, Webster P, Taddei N, Clark A, Stefani M, Ramponi G, Dobson C
      Designing conditions for in vitro formation of amyloid protofilaments and fibrils.
      Proceedings of the National Academy of Sciences of the United States of America. 1999 Mar 30;96(7):3590-4

    Consistent statements
    

    • Therapeutics to prevent Aβ oligomerization are in development. Hardy J  Selkoe D 

    Alternative statements
    

    • Therapies directed an extracellular Aβ may not target the most toxic factors. Marchesi V 
  • Young APP transgenic mice undergo synaptic, electrophysiological and behavioral changes before amyloid plaque deposition.

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

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • 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
    • 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

    Consistent statements
    

    • Transgenic mice demonstrate neurologic deficits prior to appearance of amyloid deposits. Bitan G  Kirkitadze M  Lomakin A  Vollers S  Benedek G  Teplow D 
    • Conditional knockout mice in which PS1 and PS2 are selectively inactivated in the adult cerebral cortex develop age-related, progressive neurodegeneration characterized by hallmarks of AD neuropathology, including synaptic loss, neuronal cell death, astrogliosis and tau hyperphosphorylation. Shen J  Kelleher R 

    Alternative statements
    

    • Transgenic mice that demonstrate progressive Aβ deposition often do not suffer neuronal loss. Hardy J  Selkoe D 

    Genes/Proteins
    

    • Gene: APP amyloid beta (A4) precursor protein [Homo sapiens]
  • Soluble Aβ oligomers are the principal effectors of synaptic dysfunction and loss that characterize Alzheimer Disease.

    SHOW Details   Supporting(7)   Consistent(4) 

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

    • 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
    • McLean C, Cherny R, Fraser F, Fuller S, Smith M, Beyreuther K, Bush A, Masters C
      Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease.
      Annals of neurology. 1999 Dec;46(6):860-6
    • Hartley D, Walsh D, Ye C, Diehl T, Vasquez S, Vassilev P, Teplow D, Selkoe D
      Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 1999 Oct 15;19(20):8876-84
    • Walsh D, Hartley D, Kusumoto Y, Fezoui Y, Condron M, Lomakin A, Benedek G, Selkoe D, Teplow D
      Amyloid beta-protein fibrillogenesis. Structure and biological activity of protofibrillar intermediates.
      The Journal of biological chemistry. 1999 Sep 3;274(36):25945-52
    • 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
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Chui D, Tanahashi H, Ozawa K, Ikeda S, Checler F, Ueda O, Suzuki H, Araki W, Inoue H, Shirotani K, Takahashi K, Gallyas F, Tabira T
      Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation.
      Nature medicine. 1999 May;5(5):560-4

    Consistent statements
    

    • In transgenic mouse and rat models with Aβ deposition, synaptic changes occur before plaque accumulation, evidence that gives strength to the idea that the soluble nonfibrillary species of Aβ plays a crucial role in AD pathogenesis. Dziewczapolski G  Glogowski C  Masliah E  Heinemann S 
    • Aβ may give rise to small toxic derivatives other than the highly aggregated species found in amyloid deposits. 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, diffusible Aβ oligomers can interrupt memory circuits in the brain. 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, stable Aβ oligomers have been detected in extracts of AD brain.

    SHOW Details   Supporting(2)   Consistent(7)   Alternative to: (1)    Genes/Proteins: (1)

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • McLean C, Cherny R, Fraser F, Fuller S, Smith M, Beyreuther K, Bush A, Masters C
      Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease.
      Annals of neurology. 1999 Dec;46(6):860-6

    Consistent statements
    

    • Oligomeric Aβ interaction with neurons may induce synaptic changes and cognitive impairment in young APP transgenic mice. Walsh D  Klyubin I  Fadeeva J  Cullen W  Anwyl R  Wolfe M  Rowan M  Selkoe D 
    • ApoE protein associated with soluble Aβ in CSF, plasma, brain homogenates from both control and AD patients. Holtzman D 
    • Known mutations of APP, PS-1 and PS-2 result in overproduction of Aβ42 or the Aβ42/40 ratio. Aβ42 is the predominant Aβ species initially deposited in the AD brain. Holtzman D 
    • The prominent immunoreactive Aβ oligomer (ADDLs) in soluble AD brain extracts is identified as an Aβ 12-mer. Gong Y  Chang L  Viola K  Lacor P  Lambert M  Finch C  Krafft G  Klein W 
    • Human brain levels of soluble Aβ oligomers are greatly elevated in AD. Gong Y  Chang L  Viola K  Lacor P  Lambert M  Finch C  Krafft G  Klein W 
    • In situ data from autopsied AD brain tissue parallels in vitro observations from models of neuronal beta amyloid toxicity on both morphological and biochemical levels. Cotman C  Su J 
    • Small, diffusible oligomeric assemblies of misfolded proteins may cause injury and neurodegeneration in AD, Parkinson Disease, Huntington Disease, and spinocerebellar ataxias. Hardy J  Selkoe D 

    Alternative statements
    

    • The earliest pathological event that occurs in the process of AD is probably the deposition of insoluble forms of Aβ peptide in the brain. Holtzman D 

    Genes/Proteins
    

    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • Oligomeric Aβ levels are increased by expressing AD-causing mutations of APP or presenilins.

    SHOW Details   Supporting(2)   Discussing: (1)

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Xia W, Zhang J, Kholodenko D, Citron M, Podlisny M, Teplow D, Haass C, Seubert P, Koo E, Selkoe D
      Enhanced production and oligomerization of the 42-residue amyloid beta-protein by Chinese hamster ovary cells stably expressing mutant presenilins.
      The Journal of biological chemistry. 1997 Mar 21;272(12):7977-82

    Discussing statements
    

    • Why do Aβ oligomers not cause disease in familial AD patients early on in life, since they are presumably being generated continually? Wolozin B 
  • Oligomeric Aβ formation and levels in V717F APP751 transfected cell conditioned media was reduced by treating transfected cells with γ-secretase inhibitors DAPM and MWIII-20.

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

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Consistent statements
    

    • γ-secretase inhibitors have demonstrated efficacy in animal models and are in Phase I human clinical trials. Golde T 
    • A chemical compound that inhibits the production of Aβ is used to lower the oligomers enough to completely prevent the synaptic interruption, while still leaving appreciable monomer levels (60 percent of normal). Selkoe D 

    Genes/Proteins
    

    • Protein: Presenilin-1 [Homo sapiens]
    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • Oligomeric Aβ interaction with neurons may induce synaptic changes and cognitive impairment in young APP transgenic mice.

    SHOW Details   Supporting(5)   Consistent(3) 

    Experimental Approach: Mechanism - molecular and cell,   Pathophysiology,   Neuropsychology/Behavior,   Genetics,   Mechanism - biochemistry and structural biology,   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
    • 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
    • Chen G, Chen K, Knox J, Inglis J, Bernard A, Martin S, Justice A, McConlogue L, Games D, Freedman S, Morris R
      A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's disease.
      Nature. 2000 Dec 21;408(6815):975-9
    • Chui D, Tanahashi H, Ozawa K, Ikeda S, Checler F, Ueda O, Suzuki H, Araki W, Inoue H, Shirotani K, Takahashi K, Gallyas F, Tabira T
      Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation.
      Nature medicine. 1999 May;5(5):560-4
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Consistent statements
    

    • Oligomeric Aβ, rather than fibrillar Aβ in plaques, may be the immediate cause of synaptic dysfunction and dementia in Alzheimer’s disease. Holmes C  Boche D  Wilkinson D  Yadegarfar G  Hopkins V  Bayer A  Jones R  Bullock R  Love S  Neal J  Zotova E  Nicoll J 
    • Soluble, stable Aβ oligomers have been detected in extracts of AD brain. Walsh D  Klyubin I  Fadeeva J  Cullen W  Anwyl R  Wolfe M  Rowan M  Selkoe D 
    • Small, diffusible oligomeric assemblies of misfolded proteins may cause injury and neurodegeneration in AD, Parkinson Disease, Huntington Disease, and spinocerebellar ataxias. Hardy J  Selkoe D 
  • Immunodepletion of Aβ with R1282 specifically removed Aβ monomers and oligomers from V717F APP751 conditioned media, and did not reduce amount of APPs from conditioned media.

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

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Genes/Proteins
    

    • Gene: APP amyloid beta (A4) precursor protein [Homo sapiens]
    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • Iodixanol gradient fractionation identified Aβ40 and Aβ42 monomers, dimers and trimers, suggesting that the process of oligomerization is initiated soon after the generation of Aβ in discrete intracellular vesicles.

    SHOW Details   Supporting(2) 

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

    • Xia W, Zhang J, Kholodenko D, Citron M, Podlisny M, Teplow D, Haass C, Seubert P, Koo E, Selkoe D
      Enhanced production and oligomerization of the 42-residue amyloid beta-protein by Chinese hamster ovary cells stably expressing mutant presenilins.
      The Journal of biological chemistry. 1997 Mar 21;272(12):7977-82
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
  • Soluble Aβ levels correlate strongly with extent of synaptic loss and cognitive impairment.

    SHOW Details   Supporting(3)   Consistent(4)     Genes/Proteins: (1)

    Experimental Approach: Neuropsychology/Behavior,   Mechanism - biochemistry and structural biology,   Pathophysiology
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • McLean C, Cherny R, Fraser F, Fuller S, Smith M, Beyreuther K, Bush A, Masters C
      Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease.
      Annals of neurology. 1999 Dec;46(6):860-6
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Lue L, Kuo Y, Roher A, Brachova L, Shen Y, Sue L, Beach T, Kurth J, Rydel R, Rogers J
      Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease.
      The American journal of pathology. 1999 Sep;155(3):853-62

    Consistent statements
    

    • Synthetic Aβ aggregates, termed ADDLs, are highly toxic and inhibit hippocampal function. Wolozin B 
    • Soluble, diffusible Aβ oligomers can interrupt memory circuits in the brain. 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 
    • 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 

    Genes/Proteins
    

    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • Filamentous Aβ oligomers are not detected in conditioned media of transfected V717F APP751 cells.

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

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Genes/Proteins
    

    • Gene: APP amyloid beta (A4) precursor protein [Homo sapiens]
    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • Fibrillar Aβ are neurotoxic in vitro.

    SHOW Details   Supporting(3)   Consistent(2)     Genes/Proteins: (1)

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

    • Lorenzo A, Yankner B
      Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red.
      Proceedings of the National Academy of Sciences of the United States of America. 1994 Dec 6;91(25):12243-7
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Pike C, Walencewicz A, Glabe C, Cotman C
      In vitro aging of beta-amyloid protein causes peptide aggregation and neurotoxicity.
      Brain research. 1991 Nov 1;563(1-2):311-4

    Consistent statements
    

    • Fibrillar Aβ kills cultured neurons. Gong Y  Chang L  Viola K  Lacor P  Lambert M  Finch C  Krafft G  Klein W 
    • In AD and other CNS proteinopathies some species of the aggregated misfolded protein are directly neurotoxic. Golde T  Miller V 

    Genes/Proteins
    

    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • Conditioned media of V717F APP751 transfected cells depleted of monomeric Aβ blocked LTP, suggesting that naturally secreted soluble human Aβ oligomers are specifically responsible for the block of hippocampal LTP.

    SHOW Details   Supporting(2)   Consistent(7)   Inconsistent(1) 

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

    • Qiu W, Walsh D, Ye Z, Vekrellis K, Zhang J, Podlisny M, Rosner M, Safavi A, Hersh L, Selkoe D
      Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation.
      The Journal of biological chemistry. 1998 Dec 4;273(49):32730-8
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Consistent statements
    

    • Various preparations of aggregated Aβ can inhibit LTP. Hartley D  Zhao C  Speier A  Woodard G  Li S  Li Z  Walz T 
    • A specific form of naturally secreted Aβ blocks long-term potentiation in the absence of monomers, protofibrils and fibrils, directly in living, anesthetized rats. Selkoe D 
    • Aβ oligomers applied to brain slices or injected in vivo cause failure of hippocampal LTP. Gong Y  Chang L  Viola K  Lacor P  Lambert M  Finch C  Krafft G  Klein W 
    • Aβ oligomers inhibit long term potentiation in the hippocampus. Hardy J  Selkoe D 
    • Aβ*56 has the ability to disrupt memory function directly and is the principal cause of memory decline. Lesné S  Koh M  Kotilinek L  Kayed R  Glabe C  Yang A  Gallagher M  Ashe K 
    • An additional study extends the finding that conditioned media depleted of Aβ monomers blocked LTP, by comparing the effect of size exclusion chromatography (SEC) separated monomer and oligomers, and by demonstrating that the effect can be blocked using mouse hippocampii. Walsh D 
    • ADDLs block the reversal of LTD and formation of LTP, and may lead to synapse destabilization. Gong Y  Chang L  Viola K  Lacor P  Lambert M  Finch C  Krafft G  Klein W 

    Inconsistent statements
    

    • In 6 month old 3xTg-AD mice there is no apparent extracellular Aβ, suggesting that intraneuronal Aβ accumulation is most likely responsible for the deficits in LTP observed. Smith I  Green K  LaFerla F 
• Supporting:
  • Transgenic mice overexpressing human APP have demonstrated failure of LTP maintenance, but such studies have not identified the biochemically defined assembly forms responsible for LTP failure.

    SHOW Details   Supporting(6)     Genes/Proteins: (2)

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

    • Chapman P, White G, Jones M, Cooper-Blacketer D, Marshall V, Irizarry M, Younkin L, Good M, Bliss T, Hyman B, Younkin S, Hsiao K
      Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice.
      Nature neuroscience. 1999 Mar;2(3):271-6
    • Moechars D, Dewachter I, Lorent K, Reversé D, Baekelandt V, Naidu A, Tesseur I, Spittaels K, Haute C, Checler F, Godaux E, Cordell B, Van Leuven F
      Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain.
      The Journal of biological chemistry. 1999 Mar 5;274(10):6483-92
    • 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
    • Larson J, Lynch G, Games D, Seubert P
      Alterations in synaptic transmission and long-term potentiation in hippocampal slices from young and aged PDAPP mice.
      Brain research. 1999 Sep 4;840(1-2):23-35
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Fitzjohn S, Morton R, Kuenzi F, Rosahl T, Shearman M, Lewis H, Smith D, Reynolds D, Davies C, Collingridge G, Seabrook G
      Age-related impairment of synaptic transmission but normal long-term potentiation in transgenic mice that overexpress the human APP695SWE mutant form of amyloid precursor protein.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2001 Jul 1;21(13):4691-8

    Genes/Proteins
    

    • Gene: APP amyloid beta (A4) precursor protein [Homo sapiens]
    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • The nature of the pathogenic Aβ species in the human Alzheimer Disease brain and direct demonstration of its neurobiological effects are unresolved.

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

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

    • Morgan D, Diamond D, Gottschall P, Ugen K, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D, Connor K, Hatcher J, Hope C, Gordon M, Arendash G
      A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease.
      Nature. 2000 Dec 21;408(6815):982-5
    • 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
    • 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
    • Lorenzo A, Yankner B
      Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red.
      Proceedings of the National Academy of Sciences of the United States of America. 1994 Dec 6;91(25):12243-7
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Genes/Proteins
    

    • Gene: APP amyloid beta (A4) precursor protein [Homo sapiens]
  • Tissue-transglutaminase-induced oligomeric Aβ species are resistant to both NEP and IDE, while the monomer was readily degraded by both metalloproteases.

    SHOW Details   Supporting(2)   Consistent(1)     Genes/Proteins: (3)

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

    • Tanzi R, Moir R, Wagner S
      Clearance of Alzheimer's Abeta peptide: the many roads to perdition.
      Neuron. 2004 Sep 2;43(5):605-8
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Consistent statements
    

    • IDE is only able to degrade Aβ monomers. Tanzi R  Moir R  Wagner S 

    Genes/Proteins
    

    • Protein: Protein-glutamine gamma-glutamyltransferase 2 [Homo sapiens]
    • Protein: Neprilysin [Homo sapiens]
    • Protein: Insulin-degrading enzyme [Homo sapiens]
  • LTP is a measure of synaptic plasticity that is disrupted by synthetic Aβ.

    SHOW Details   Supporting(2)   Consistent(2) 

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Kim J, Anwyl R, Suh Y, Djamgoz M, Rowan M
      Use-dependent effects of amyloidogenic fragments of (beta)-amyloid precursor protein on synaptic plasticity in rat hippocampus in vivo.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2001 Feb 15;21(4):1327-33

    Consistent statements
    

    • Aβ oligomers inhibit long term potentiation in the hippocampus. Hardy J  Selkoe D 
    • ADDLs block the reversal of LTD and formation of LTP, and may lead to synapse destabilization. Gong Y  Chang L  Viola K  Lacor P  Lambert M  Finch C  Krafft G  Klein W 
  • Soluble, stable Aβ oligomers can be produced by cultured cells.

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

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Walsh D, Tseng B, Rydel R, Podlisny M, Selkoe D
      The oligomerization of amyloid beta-protein begins intracellularly in cells derived from human brain.
      Biochemistry. 2000 Sep 5;39(35):10831-9
    • Morishima-Kawashima M, Ihara Y
      The presence of amyloid beta-protein in the detergent-insoluble membrane compartment of human neuroblastoma cells.
      Biochemistry. 1998 Nov 3;37(44):15247-53
    • Podlisny M, Ostaszewski B, Squazzo S, Koo E, Rydell R, Teplow D, Selkoe D
      Aggregation of secreted amyloid beta-protein into sodium dodecyl sulfate-stable oligomers in cell culture.
      The Journal of biological chemistry. 1995 Apr 21;270(16):9564-70

    Genes/Proteins
    

    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • Relevant Aβ toxicity has barely been demonstrated, and none of the data amounts to convincing support that Aβ toxicity causes massive cell loss seen in Alzheimer Disease.

    SHOW Details   Supporting(6)   Consistent(1)   Alternative to: (1)    Genes/Proteins: (1)

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

    • Wang H, Pasternak J, Kuo H, Ristic H, Lambert M, Chromy B, Viola K, Klein W, Stine W, Krafft G, Trommer B
      Soluble oligomers of beta amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus.
      Brain research. 2002 Jan 11;924(2):133-40
    • Janus C, Pearson J, McLaurin J, Mathews P, Jiang Y, Schmidt S, Chishti M, Horne P, Heslin D, French J, Mount H, Nixon R, Mercken M, Bergeron C, Fraser P, St George-Hyslop P, Westaway D
      A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease.
      Nature. 2000 Dec 21;408(6815):979-82
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Meyer-Luehmann M, Spires-Jones T, Prada C, Garcia-Alloza M, de Calignon A, Rozkalne A, Koenigsknecht-Talboo J, Holtzman D, Bacskai B, Hyman B
      Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease.
      Nature. 2008 Feb 7;451(7179):720-4
    • Morgan D, Diamond D, Gottschall P, Ugen K, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D, Connor K, Hatcher J, Hope C, Gordon M, Arendash G
      A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease.
      Nature. 2000 Dec 21;408(6815):982-5
    • 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

    Consistent statements
    

    • Mouse models overexpressing mutant human APP have reproduced overproduction of Aβ peptides and progressive amyloid deposition, but they have largely failed to reproduce neurodegeneration. Shen J  Kelleher R 

    Alternative statements
    

    • Aβ deposition has not been found to be toxic or cause damage and death of nerve cells in human or animal brain. Aliev G 

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
  • Conditioned media from V717F APP751 transfected cells completely blocked LTP whereas untransfected cell conditioned media had no effect.

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

    Experimental Approach: Pathophysiology,   Mechanism - molecular and cell,   Genetics,   Mechanism - physiological systems,  
    Pathogenic Narrative Tags: Pathogenic event
    Supporting Evidence
    

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Consistent statements
    

    • Previous studies have demonstrated that a soluble non-fibrillar form of Aβ could alter LTP. Walsh D 

    Genes/Proteins
    

    • Gene: APP amyloid beta (A4) precursor protein [Homo sapiens]
    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • Microsomes isolated from cells expressing V717F mutant APP751 contain Aβ monomers and oligomers.

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

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Genes/Proteins
    

    • Gene: APP amyloid beta (A4) precursor protein [Homo sapiens]
    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • Aggregated Aβ in the form of plaques may be harmless, or could even be protective, and therefore the process of removing them might be counterproductive, by generating an increased concentration of toxic oligomeric Aβ.

    SHOW Details   Supporting(3)     Genes/Proteins: (1)

    Experimental Approach: Biomarkers,   Pathophysiology,   Target validation,   Mechanism - molecular and cell
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Lesné S, Koh M, Kotilinek L, Kayed R, Glabe C, Yang A, Gallagher M, Ashe K
      A specific amyloid-beta protein assembly in the brain impairs memory.
      Nature. 2006 Mar 16;440(7082):352-7
    • Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones R, Bullock R, Love S, Neal J, Zotova E, Nicoll J
      Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial.
      Lancet. 2008 Jul 19;372(9634):216-23
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
  • Aβ assemblies [in animal models] can mimic some of the symptomatology of AD, including alterations in synaptic function, memory and learning, and behavior, suggesting their early involvement in the progression of AD.

    SHOW Details   Supporting(10) 

    Experimental Approach: Mechanism - molecular and cell,   Neuropsychology/Behavior,   Mechanism - biochemistry and structural biology,   Animal models
    Pathogenic Narrative Tags: Pathogenic event
    Supporting Evidence
    

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Ye C, Selkoe D, Hartley D
      Protofibrils of amyloid beta-protein inhibit specific K+ currents in neocortical cultures.
      Neurobiology of disease. 2003 Aug;13(3):177-90
    • Lesné S, Koh M, Kotilinek L, Kayed R, Glabe C, Yang A, Gallagher M, Ashe K
      A specific amyloid-beta protein assembly in the brain impairs memory.
      Nature. 2006 Mar 16;440(7082):352-7
    • Wang Q, Rowan M, Anwyl R
      Beta-amyloid-mediated inhibition of NMDA receptor-dependent long-term potentiation induction involves activation of microglia and stimulation of inducible nitric oxide synthase and superoxide.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2004 Jul 7;24(27):6049-56
    • 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
    • Wang H, Pasternak J, Kuo H, Ristic H, Lambert M, Chromy B, Viola K, Klein W, Stine W, Krafft G, Trommer B
      Soluble oligomers of beta amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus.
      Brain research. 2002 Jan 11;924(2):133-40
    • Walsh D, Townsend M, Podlisny M, Shankar G, Fadeeva J, El Agnaf O, Hartley D, Selkoe D
      Certain inhibitors of synthetic amyloid beta-peptide (Abeta) fibrillogenesis block oligomerization of natural Abeta and thereby rescue long-term potentiation.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2005 Mar 9;25(10):2455-62
    • Ye C, Walsh D, Selkoe D, Hartley D
      Amyloid beta-protein induced electrophysiological changes are dependent on aggregation state: N-methyl-D-aspartate (NMDA) versus non-NMDA receptor/channel activation.
      Neuroscience letters. 2004 Aug 19;366(3):320-5
    • Kawahara M, Kuroda Y, Arispe N, Rojas E
      Alzheimer's beta-amyloid, human islet amylin, and prion protein fragment evoke intracellular free calcium elevations by a common mechanism in a hypothalamic GnRH neuronal cell line.
      The Journal of biological chemistry. 2000 May 12;275(19):14077-83
    • Klyubin I, Walsh D, Cullen W, Fadeeva J, Anwyl R, Selkoe D, Rowan M
      Soluble Arctic amyloid beta protein inhibits hippocampal long-term potentiation in vivo.
      The European journal of neuroscience. 2004 May;19(10):2839-46
  • Incubation of V717F APP751 transfected cell conditioned media with insulin degrading enzyme selectively degraded and removed monomeric Aβ leaving Aβ oligomers unchanged.

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

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Consistent statements
    

    • IDE is only able to degrade Aβ monomers. Tanzi R  Moir R  Wagner S 

    Genes/Proteins
    

    • Gene: APP amyloid beta (A4) precursor protein [Homo sapiens]
    • Gene: IDE insulin-degrading enzyme [Homo sapiens]
    • Protein: Amyloid beta A4 protein [Homo sapiens]
    • Protein: Insulin-degrading enzyme [Homo sapiens]
  • Conditioned media from V717F APP751 transfected cells did not affect baseline transmission in the absence of high-frequency stimulation.

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

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Consistent statements
    

    • Additional studies have confirmed that conditioned media from V717F APP751 transfected cells does not alter baseline transmission, using mouse hippocampal slice cultures in vitro. Walsh D 

    Genes/Proteins
    

    • Gene: APP amyloid beta (A4) precursor protein [Homo sapiens]
    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • Immunodepletion-induced prevention of LTP blockage was not due to a non-specific effect of R1282 present in the V717F APP751 conditioned media, since R1282 added to untransfected cell conditioned media had no effect on LTP.

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

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Genes/Proteins
    

    • Gene: APP amyloid beta (A4) precursor protein [Homo sapiens]
    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • Oligomeric Aβ, rather than fibrillar Aβ in plaques, may be the immediate cause of synaptic dysfunction and dementia in Alzheimer’s disease.

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

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

    • Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones R, Bullock R, Love S, Neal J, Zotova E, Nicoll J
      Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial.
      Lancet. 2008 Jul 19;372(9634):216-23
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Lesné S, Koh M, Kotilinek L, Kayed R, Glabe C, Yang A, Gallagher M, Ashe K
      A specific amyloid-beta protein assembly in the brain impairs memory.
      Nature. 2006 Mar 16;440(7082):352-7

    Consistent statements
    

    • Oligomeric Aβ interaction with neurons may induce synaptic changes and cognitive impairment in young APP transgenic mice. Walsh D  Klyubin I  Fadeeva J  Cullen W  Anwyl R  Wolfe M  Rowan M  Selkoe D 
    • Oligomeric amyloid beta ligands (ADDLs) are a molecular basis for reversible memory loss. Gong Y  Chang L  Lambert M  Klein W  Lacor P  Finch C  Krafft G  Viola K 

    Alternative statements
    

    • Aβ deposition has not been found to be toxic or cause damage and death of nerve cells in human or animal brain. Aliev G 

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
  • Fibrillar plaque density correlates weakly with severity of dementia in AD.

    SHOW Details   Supporting(3)   Consistent(4)   Inconsistent(2)   Alternative to: (2)

    Experimental Approach: Pathophysiology,   Mechanism - biochemistry and structural biology,   Neuropsychology/Behavior
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Dickson D, Crystal H, Bevona C, Honer W, Vincent I, Davies P
      Correlations of synaptic and pathological markers with cognition of the elderly.
      Neurobiology of aging. 1995;16(3):285-98; discussion 298-304
    • Terry R, Masliah E, Salmon D, Butters N, DeTeresa R, Hill R, Hansen L, Katzman R
      Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment.
      Annals of neurology. 1991 Oct;30(4):572-80

    Consistent statements
    

    • In transgenic mouse and rat models with Aβ deposition, synaptic changes occur before plaque accumulation, evidence that gives strength to the idea that the soluble nonfibrillary species of Aβ plays a crucial role in AD pathogenesis. Dziewczapolski G  Glogowski C  Masliah E  Heinemann S 
    • 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 
    • A fundamental tenet of the amyloid hypothesis of Alzheimer’s disease is that the deposition of amyloid-beta precedes and induces the neuronal abnormalities that underlie dementia. Meyer-Luehmann M  Spires-Jones T  Prada C  Garcia-Alloza M  de Calignon A  Rozkalne A  Koenigsknecht-Talboo J  Holtzman D  Bacskai B  Hyman B 

    Alternative statements
    

    • The degree of dementia in AD correlates with concentration of soluble Aβ. Hardy J  Selkoe D 
    • The earliest pathological event that occurs in the process of AD is probably the deposition of insoluble forms of Aβ peptide in the brain. Holtzman D 
  • Should Aβ assemblies be physiologically active, their persistence could increase their contribution to the progressive neurodegeneration process observed in AD.

    SHOW Details   Supporting(6) 

    Experimental Approach: 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
    • Townsend M, Shankar G, Mehta T, Walsh D, Selkoe D
      Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity: a potent role for trimers.
      The Journal of physiology. 2006 Apr 15;572(Pt 2):477-92
    • Ye C, Walsh D, Selkoe D, Hartley D
      Amyloid beta-protein induced electrophysiological changes are dependent on aggregation state: N-methyl-D-aspartate (NMDA) versus non-NMDA receptor/channel activation.
      Neuroscience letters. 2004 Aug 19;366(3):320-5
    • Ye C, Selkoe D, Hartley D
      Protofibrils of amyloid beta-protein inhibit specific K+ currents in neocortical cultures.
      Neurobiology of disease. 2003 Aug;13(3):177-90
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Hartley D, Walsh D, Ye C, Diehl T, Vasquez S, Vassilev P, Teplow D, Selkoe D
      Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 1999 Oct 15;19(20):8876-84
  • Aβ oligomers applied to brain slices or injected in vivo cause failure of hippocampal LTP.

    SHOW Details   Supporting(4)   Consistent(4)   Inconsistent(1) 

    Experimental Approach: Animal models,   Mechanism - physiological systems,   Pathophysiology
    Pathogenic Narrative Tags: Pathogenic event
    Supporting Evidence
    

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Wang H, Pasternak J, Kuo H, Ristic H, Lambert M, Chromy B, Viola K, Klein W, Stine W, Krafft G, Trommer B
      Soluble oligomers of beta amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus.
      Brain research. 2002 Jan 11;924(2):133-40
    • 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

    Consistent statements
    

    • Synthetic Aβ aggregates, termed ADDLs, are highly toxic and inhibit hippocampal function. Wolozin B 
    • Various preparations of aggregated Aβ can inhibit LTP. Hartley D  Zhao C  Speier A  Woodard G  Li S  Li Z  Walz T 
    • Aβ oligomers inhibit long term potentiation in the hippocampus. Hardy J  Selkoe D 
    • Conditioned media of V717F APP751 transfected cells depleted of monomeric Aβ blocked LTP, suggesting that naturally secreted soluble human Aβ oligomers are specifically responsible for the block of hippocampal LTP. Walsh D  Klyubin I  Fadeeva J  Cullen W  Anwyl R  Wolfe M  Rowan M  Selkoe D 

    Inconsistent statements
    

    • In 6 month old 3xTg-AD mice there is no apparent extracellular Aβ, suggesting that intraneuronal Aβ accumulation is most likely responsible for the deficits in LTP observed. Smith I  Green K  LaFerla F 
  • Immunodepletion of Aβ from V717F APP751 conditioned media using R1282 antibody completely prevented the block of LTP.

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

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Genes/Proteins
    

    • Gene: APP amyloid beta (A4) precursor protein [Homo sapiens]
    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • At nanomolar concentrations, soluble Aβ oligomers block hippocampal long-term potentiation.

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

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Genes/Proteins
    

    • Gene: APP amyloid beta (A4) precursor protein [Homo sapiens]
  • Aβ oligomer amounts are not reduced with previous trypsinization of intact cells, supporting their intracellular origin.

    SHOW Details   Supporting(1) 

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
  • LTP of excitatory synaptic transmission in the CA1 region is induced by high-frequency stimulation.

    SHOW Details   Supporting(1) 

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
  • Inhibition of hippocampal LTP in vivo is specifically due to presence of oligomeric Aβ, not monomers or fibrils.

    SHOW Details   Supporting(1)   Consistent(3) 

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Consistent statements
    

    • A specific form of naturally secreted Aβ blocks long-term potentiation in the absence of monomers, protofibrils and fibrils, directly in living, anesthetized rats. Selkoe D 
    • Previous studies have demonstrated that a soluble non-fibrillar form of Aβ could alter LTP. Walsh D 
    • A chemical compound that inhibits the production of Aβ is used to lower the oligomers enough to completely prevent the synaptic interruption, while still leaving appreciable monomer levels (60 percent of normal). Selkoe D 
  • Soluble oligomers of Aβ are neurotoxic in vitro and in vivo.

    SHOW Details   Supporting(8)   Consistent(1) 

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

    • Walsh D, Lomakin A, Benedek G, Condron M, Teplow D
      Amyloid beta-protein fibrillogenesis. Detection of a protofibrillar intermediate.
      The Journal of biological chemistry. 1997 Aug 29;272(35):22364-72
    • Harper J, Wong S, Lieber C, Lansbury P
      Observation of metastable Abeta amyloid protofibrils by atomic force microscopy.
      Chemistry & biology. 1997 Feb;4(2):119-25
    • Oda T, Wals P, Osterburg H, Johnson S, Pasinetti G, Morgan T, Rozovsky I, Stine W, Snyder S, Holzman T
      Clusterin (apoJ) alters the aggregation of amyloid beta-peptide (A beta 1-42) and forms slowly sedimenting A beta complexes that cause oxidative stress.
      Experimental neurology. 1995 Nov;136(1):22-31
    • Nilsberth C, Westlind-Danielsson A, Eckman C, Condron M, Axelman K, Forsell C, Stenh C, Luthman J, Teplow D, Younkin S, Näslund J, Lannfelt L
      The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation.
      Nature neuroscience. 2001 Sep;4(9):887-93
    • Hartley D, Walsh D, Ye C, Diehl T, Vasquez S, Vassilev P, Teplow D, Selkoe D
      Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 1999 Oct 15;19(20):8876-84
    • 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
    • Walsh D, Hartley D, Kusumoto Y, Fezoui Y, Condron M, Lomakin A, Benedek G, Selkoe D, Teplow D
      Amyloid beta-protein fibrillogenesis. Structure and biological activity of protofibrillar intermediates.
      The Journal of biological chemistry. 1999 Sep 3;274(36):25945-52
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Consistent statements
    

    • Several lines of evidence indicate that smaller Aβ oligomers, rather than full-fledged fibrils, may be the primary neurotoxic form. Tycko R 
  • Oligomer-depleted conditioned media did not block hippocampal LTP despite maintenance of significant levels of monomeric Aβ.

    SHOW Details   Supporting(1)   Consistent(2) 

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Consistent statements
    

    • An additional study extends the finding that conditioned media depleted of Aβ monomers blocked LTP, by comparing the effect of size exclusion chromatography (SEC) separated monomer and oligomers, and by demonstrating that the effect can be blocked using mouse hippocampii. Walsh D 
    • A chemical compound that inhibits the production of Aβ is used to lower the oligomers enough to completely prevent the synaptic interruption, while still leaving appreciable monomer levels (60 percent of normal). Selkoe D 
  • Aβ oligomers are composed of Aβ40 and Aβ42.

    SHOW Details   Supporting(2) 

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

    • Podlisny M, Ostaszewski B, Squazzo S, Koo E, Rydell R, Teplow D, Selkoe D
      Aggregation of secreted amyloid beta-protein into sodium dodecyl sulfate-stable oligomers in cell culture.
      The Journal of biological chemistry. 1995 Apr 21;270(16):9564-70
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
  • Neuritic plaques are relevant to AD.

    SHOW Details   Supporting(11)   Consistent(1) 

    Description: Neuritic plaques have been considered as a probable cause of neuronal degeneration and death in AD long before the discovery that plaques contain Aβ. Since then, evidence has accumulated indicating that Aβ may be responsible – at least in part – for the pathology and symptoms of AD. It appeared that the oligomerization state of the peptide is highly relevant to Aβ toxicity. Aβ is generated from APP likely as monomer, while mature plaques contain Aβ fibrils, which form as a result of peptide aggregation. Between monomers and fibrils, there are many oligomeric forms – from dimers and trimers to Aβ-derived diffusible ligands (ADDLs), annular assemblies, and protofibrils (the latter forms being mainly the result of in vitro polymerization). Recent work has shown that it is the presence of the soluble Aβ oligomers (dimers, trimers, or higher oligomers, such as Aβ*56) rather than the fibrillar Aβ and the brain plaque load which correlates with the learning and memory deficits, in mouse models of AD. If the fibrillar Aβ present in mature plaques is less toxic than the oligomers, then are the neuritic plaques less relevant to AD pathology than the soluble Aβ oligomers? Not at all! Recent studies suggest that the plaques might function as reservoirs of the highly pathogenic, smaller Aβ oligomers, from which they can be released.
    Experimental Approach: Mechanism - biochemistry and structural biology,  
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Shankar G, Li S, Mehta T, Garcia-Munoz A, Shepardson N, Smith I, Brett F, Farrell M, Rowan M, Lemere C, Regan C, Walsh D, Sabatini B, Selkoe D
      Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory.
      Nature medicine. 2008 Aug;14(8):837-42
    • LaFerla F, Green K, Oddo S
      Intracellular amyloid-beta in Alzheimer's disease.
      Nature reviews. Neuroscience. 2007 Jul;8(7):499-509
    • Glenner G, Wong C
      Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein.
      Biochemical and biophysical research communications. 1984 May 16;120(3):885-90
    • Cleary J, Walsh D, Hofmeister J, Shankar G, Kuskowski M, Selkoe D, Ashe K
      Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function.
      Nature neuroscience. 2005 Jan;8(1):79-84
    • Lesné S, Koh M, Kotilinek L, Kayed R, Glabe C, Yang A, Gallagher M, Ashe K
      A specific amyloid-beta protein assembly in the brain impairs memory.
      Nature. 2006 Mar 16;440(7082):352-7
    • Martins I, Kuperstein I, Wilkinson H, Maes E, Vanbrabant M, Jonckheere W, Van Gelder P, Hartmann D, D'Hooge R, De Strooper B, Schymkowitz J, Rousseau F
      Lipids revert inert Abeta amyloid fibrils to neurotoxic protofibrils that affect learning in mice.
      The EMBO journal. 2008 Jan 9;27(1):224-33
    • 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
    • Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R
      APP processing and synaptic function.
      Neuron. 2003 Mar 27;37(6):925-37
    • 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
    • Masters C, Simms G, Weinman N, Multhaup G, McDonald B, Beyreuther K
      Amyloid plaque core protein in Alzheimer disease and Down syndrome.
      Proceedings of the National Academy of Sciences of the United States of America. 1985 Jun;82(12):4245-9

    Consistent statements
    

    • The invariant accumulation of insoluble amyloid plaques in AD may signify that they serve as relatively inert reservoirs of small bioactive oligomers, and they may disassemble more readily in the presence of lipids. Shankar G  Li S  Mehta T  Garcia-Munoz A  Shepardson N  Smith I  Brett F  Farrell M  Rowan M  Lemere C  Regan C  Walsh D  Sabatini B  Selkoe D 
  • It is possible that submicroscopic nuclei may be present in the cortex perhaps related to the recently reported amyloid-beta oligomeric forms, as precursors to this sudden growth.

    SHOW Details   Supporting(3)   Consistent(1)   Alternative to: (1)    Genes/Proteins: (1)

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

    • Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C, Kilger E, Neuenschwander A, Abramowski D, Frey P, Jaton A, Vigouret J, Paganetti P, Walsh D, Mathews P, Ghiso J, Staufenbiel M, Walker L, Jucker M
      Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host.
      Science (New York, N.Y.). 2006 Sep 22;313(5794):1781-4
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Lesné S, Koh M, Kotilinek L, Kayed R, Glabe C, Yang A, Gallagher M, Ashe K
      A specific amyloid-beta protein assembly in the brain impairs memory.
      Nature. 2006 Mar 16;440(7082):352-7

    Consistent statements
    

    • Some of the punctate blue staining might potentially be “sub-microscopic” dense plaques. Kumar-Singh S 

    Alternative statements
    

    • Live multiphoton imaging cannot yet visualize the prior accumulation of Aβ or the nucleation event. Lansbury P 

    Genes/Proteins
    

    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • Aβ-lowering compounds that prevent intra- or extracellular oligomerization would be an attractive therapeutic approach to selectively reduce synaptotoxicity.

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

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Rochet J, Lansbury P
      Amyloid fibrillogenesis: themes and variations.
      Current opinion in structural biology. 2000 Feb;10(1):60-8
    • Chiti F, Webster P, Taddei N, Clark A, Stefani M, Ramponi G, Dobson C
      Designing conditions for in vitro formation of amyloid protofilaments and fibrils.
      Proceedings of the National Academy of Sciences of the United States of America. 1999 Mar 30;96(7):3590-4

    Consistent statements
    

    • Therapeutics to prevent Aβ oligomerization are in development. Hardy J  Selkoe D 

    Alternative statements
    

    • Therapies directed an extracellular Aβ may not target the most toxic factors. Marchesi V 
  • Young APP transgenic mice undergo synaptic, electrophysiological and behavioral changes before amyloid plaque deposition.

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

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • 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
    • 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

    Consistent statements
    

    • Transgenic mice demonstrate neurologic deficits prior to appearance of amyloid deposits. Bitan G  Kirkitadze M  Lomakin A  Vollers S  Benedek G  Teplow D 
    • Conditional knockout mice in which PS1 and PS2 are selectively inactivated in the adult cerebral cortex develop age-related, progressive neurodegeneration characterized by hallmarks of AD neuropathology, including synaptic loss, neuronal cell death, astrogliosis and tau hyperphosphorylation. Shen J  Kelleher R 

    Alternative statements
    

    • Transgenic mice that demonstrate progressive Aβ deposition often do not suffer neuronal loss. Hardy J  Selkoe D 

    Genes/Proteins
    

    • Gene: APP amyloid beta (A4) precursor protein [Homo sapiens]
  • Aβ oligomers are sufficient to induce cell cycle re-entry in neurons.

    SHOW Details   Supporting(7)     Genes/Proteins: (1)

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

    • Lambert M, Velasco P, Chang L, Viola K, Fernandez S, Lacor P, Khuon D, Gong Y, Bigio E, Shaw P, De Felice F, Krafft G, Klein W
      Monoclonal antibodies that target pathological assemblies of Abeta.
      Journal of neurochemistry. 2007 Jan;100(1):23-35
    • Lesné S, Koh M, Kotilinek L, Kayed R, Glabe C, Yang A, Gallagher M, Ashe K
      A specific amyloid-beta protein assembly in the brain impairs memory.
      Nature. 2006 Mar 16;440(7082):352-7
    • Lacor P, Buniel M, Furlow P, Clemente A, Velasco P, Wood M, Viola K, Klein W
      Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2007 Jan 24;27(4):796-807
    • Wang H, Pasternak J, Kuo H, Ristic H, Lambert M, Chromy B, Viola K, Klein W, Stine W, Krafft G, Trommer B
      Soluble oligomers of beta amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus.
      Brain research. 2002 Jan 11;924(2):133-40
    • Varvel N, Bhaskar K, Patil A, Pimplikar S, Herrup K, Lamb B
      Abeta oligomers induce neuronal cell cycle events in Alzheimer's disease.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2008 Oct 22;28(43):10786-93
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Wu Q, Combs C, Cannady S, Geldmacher D, Herrup K
      Beta-amyloid activated microglia induce cell cycling and cell death in cultured cortical neurons.
      Neurobiology of aging. 2000;21(6):797-806

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
  • Soluble Aβ oligomers are the principal effectors of synaptic dysfunction and loss that characterize Alzheimer Disease.

    SHOW Details   Supporting(7)   Consistent(4) 

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

    • 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
    • McLean C, Cherny R, Fraser F, Fuller S, Smith M, Beyreuther K, Bush A, Masters C
      Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease.
      Annals of neurology. 1999 Dec;46(6):860-6
    • Hartley D, Walsh D, Ye C, Diehl T, Vasquez S, Vassilev P, Teplow D, Selkoe D
      Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 1999 Oct 15;19(20):8876-84
    • Walsh D, Hartley D, Kusumoto Y, Fezoui Y, Condron M, Lomakin A, Benedek G, Selkoe D, Teplow D
      Amyloid beta-protein fibrillogenesis. Structure and biological activity of protofibrillar intermediates.
      The Journal of biological chemistry. 1999 Sep 3;274(36):25945-52
    • 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
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Chui D, Tanahashi H, Ozawa K, Ikeda S, Checler F, Ueda O, Suzuki H, Araki W, Inoue H, Shirotani K, Takahashi K, Gallyas F, Tabira T
      Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation.
      Nature medicine. 1999 May;5(5):560-4

    Consistent statements
    

    • In transgenic mouse and rat models with Aβ deposition, synaptic changes occur before plaque accumulation, evidence that gives strength to the idea that the soluble nonfibrillary species of Aβ plays a crucial role in AD pathogenesis. Dziewczapolski G  Glogowski C  Masliah E  Heinemann S 
    • Aβ may give rise to small toxic derivatives other than the highly aggregated species found in amyloid deposits. 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, diffusible Aβ oligomers can interrupt memory circuits in the brain. 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, stable Aβ oligomers have been detected in extracts of AD brain.

    SHOW Details   Supporting(2)   Consistent(7)   Alternative to: (1)    Genes/Proteins: (1)

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • McLean C, Cherny R, Fraser F, Fuller S, Smith M, Beyreuther K, Bush A, Masters C
      Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease.
      Annals of neurology. 1999 Dec;46(6):860-6

    Consistent statements
    

    • Oligomeric Aβ interaction with neurons may induce synaptic changes and cognitive impairment in young APP transgenic mice. Walsh D  Klyubin I  Fadeeva J  Cullen W  Anwyl R  Wolfe M  Rowan M  Selkoe D 
    • ApoE protein associated with soluble Aβ in CSF, plasma, brain homogenates from both control and AD patients. Holtzman D 
    • Known mutations of APP, PS-1 and PS-2 result in overproduction of Aβ42 or the Aβ42/40 ratio. Aβ42 is the predominant Aβ species initially deposited in the AD brain. Holtzman D 
    • The prominent immunoreactive Aβ oligomer (ADDLs) in soluble AD brain extracts is identified as an Aβ 12-mer. Gong Y  Chang L  Viola K  Lacor P  Lambert M  Finch C  Krafft G  Klein W 
    • Human brain levels of soluble Aβ oligomers are greatly elevated in AD. Gong Y  Chang L  Viola K  Lacor P  Lambert M  Finch C  Krafft G  Klein W 
    • In situ data from autopsied AD brain tissue parallels in vitro observations from models of neuronal beta amyloid toxicity on both morphological and biochemical levels. Cotman C  Su J 
    • Small, diffusible oligomeric assemblies of misfolded proteins may cause injury and neurodegeneration in AD, Parkinson Disease, Huntington Disease, and spinocerebellar ataxias. Hardy J  Selkoe D 

    Alternative statements
    

    • The earliest pathological event that occurs in the process of AD is probably the deposition of insoluble forms of Aβ peptide in the brain. Holtzman D 

    Genes/Proteins
    

    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • Oligomeric Aβ levels are increased by expressing AD-causing mutations of APP or presenilins.

    SHOW Details   Supporting(2)   Discussing: (1)

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Xia W, Zhang J, Kholodenko D, Citron M, Podlisny M, Teplow D, Haass C, Seubert P, Koo E, Selkoe D
      Enhanced production and oligomerization of the 42-residue amyloid beta-protein by Chinese hamster ovary cells stably expressing mutant presenilins.
      The Journal of biological chemistry. 1997 Mar 21;272(12):7977-82

    Discussing statements
    

    • Why do Aβ oligomers not cause disease in familial AD patients early on in life, since they are presumably being generated continually? Wolozin B 
  • Oligomeric Aβ interaction with neurons may induce synaptic changes and cognitive impairment in young APP transgenic mice.

    SHOW Details   Supporting(5)   Consistent(3) 

    Experimental Approach: Mechanism - molecular and cell,   Pathophysiology,   Neuropsychology/Behavior,   Genetics,   Mechanism - biochemistry and structural biology,   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
    • 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
    • Chen G, Chen K, Knox J, Inglis J, Bernard A, Martin S, Justice A, McConlogue L, Games D, Freedman S, Morris R
      A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's disease.
      Nature. 2000 Dec 21;408(6815):975-9
    • Chui D, Tanahashi H, Ozawa K, Ikeda S, Checler F, Ueda O, Suzuki H, Araki W, Inoue H, Shirotani K, Takahashi K, Gallyas F, Tabira T
      Transgenic mice with Alzheimer presenilin 1 mutations show accelerated neurodegeneration without amyloid plaque formation.
      Nature medicine. 1999 May;5(5):560-4
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Consistent statements
    

    • Oligomeric Aβ, rather than fibrillar Aβ in plaques, may be the immediate cause of synaptic dysfunction and dementia in Alzheimer’s disease. Holmes C  Boche D  Wilkinson D  Yadegarfar G  Hopkins V  Bayer A  Jones R  Bullock R  Love S  Neal J  Zotova E  Nicoll J 
    • Soluble, stable Aβ oligomers have been detected in extracts of AD brain. Walsh D  Klyubin I  Fadeeva J  Cullen W  Anwyl R  Wolfe M  Rowan M  Selkoe D 
    • Small, diffusible oligomeric assemblies of misfolded proteins may cause injury and neurodegeneration in AD, Parkinson Disease, Huntington Disease, and spinocerebellar ataxias. Hardy J  Selkoe D 
  • Oligomeric Aβ formation and levels in V717F APP751 transfected cell conditioned media was reduced by treating transfected cells with γ-secretase inhibitors DAPM and MWIII-20.

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

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Consistent statements
    

    • γ-secretase inhibitors have demonstrated efficacy in animal models and are in Phase I human clinical trials. Golde T 
    • A chemical compound that inhibits the production of Aβ is used to lower the oligomers enough to completely prevent the synaptic interruption, while still leaving appreciable monomer levels (60 percent of normal). Selkoe D 

    Genes/Proteins
    

    • Protein: Presenilin-1 [Homo sapiens]
    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • Immunodepletion of Aβ with R1282 specifically removed Aβ monomers and oligomers from V717F APP751 conditioned media, and did not reduce amount of APPs from conditioned media.

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

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Genes/Proteins
    

    • Gene: APP amyloid beta (A4) precursor protein [Homo sapiens]
    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • Iodixanol gradient fractionation identified Aβ40 and Aβ42 monomers, dimers and trimers, suggesting that the process of oligomerization is initiated soon after the generation of Aβ in discrete intracellular vesicles.

    SHOW Details   Supporting(2) 

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

    • Xia W, Zhang J, Kholodenko D, Citron M, Podlisny M, Teplow D, Haass C, Seubert P, Koo E, Selkoe D
      Enhanced production and oligomerization of the 42-residue amyloid beta-protein by Chinese hamster ovary cells stably expressing mutant presenilins.
      The Journal of biological chemistry. 1997 Mar 21;272(12):7977-82
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
  • Various preparations of aggregated Aβ can inhibit LTP.

    SHOW Details   Supporting(8)   Consistent(4)   Alternative to: (1)

    Experimental Approach: Mechanism - physiological systems
    Pathogenic Narrative Tags: Pathogenic event
    Supporting Evidence
    

    • Lesné S, Koh M, Kotilinek L, Kayed R, Glabe C, Yang A, Gallagher M, Ashe K
      A specific amyloid-beta protein assembly in the brain impairs memory.
      Nature. 2006 Mar 16;440(7082):352-7
    • Wang H, Pasternak J, Kuo H, Ristic H, Lambert M, Chromy B, Viola K, Klein W, Stine W, Krafft G, Trommer B
      Soluble oligomers of beta amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus.
      Brain research. 2002 Jan 11;924(2):133-40
    • Townsend M, Shankar G, Mehta T, Walsh D, Selkoe D
      Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity: a potent role for trimers.
      The Journal of physiology. 2006 Apr 15;572(Pt 2):477-92
    • 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
    • Walsh D, Townsend M, Podlisny M, Shankar G, Fadeeva J, El Agnaf O, Hartley D, Selkoe D
      Certain inhibitors of synthetic amyloid beta-peptide (Abeta) fibrillogenesis block oligomerization of natural Abeta and thereby rescue long-term potentiation.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2005 Mar 9;25(10):2455-62
    • Klyubin I, Walsh D, Cullen W, Fadeeva J, Anwyl R, Selkoe D, Rowan M
      Soluble Arctic amyloid beta protein inhibits hippocampal long-term potentiation in vivo.
      The European journal of neuroscience. 2004 May;19(10):2839-46
    • Hartley D, Zhao C, Speier A, Woodard G, Li S, Li Z, Walz T
      Transglutaminase Induces Protofibril-like Amyloid {beta}-Protein Assemblies That Are Protease-resistant and Inhibit Long-term Potentiation.
      The Journal of biological chemistry. 2008 Jun 13;283(24):16790-800
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Consistent statements
    

    • Aβ oligomers applied to brain slices or injected in vivo cause failure of hippocampal LTP. Gong Y  Chang L  Viola K  Lacor P  Lambert M  Finch C  Krafft G  Klein W 
    • Aβ*56 has the ability to disrupt memory function directly and is the principal cause of memory decline. Lesné S  Koh M  Kotilinek L  Kayed R  Glabe C  Yang A  Gallagher M  Ashe K 
    • Conditioned media of V717F APP751 transfected cells depleted of monomeric Aβ blocked LTP, suggesting that naturally secreted soluble human Aβ oligomers are specifically responsible for the block of hippocampal LTP. Walsh D  Klyubin I  Fadeeva J  Cullen W  Anwyl R  Wolfe M  Rowan M  Selkoe D 
    • ADDLs block the reversal of LTD and formation of LTP, and may lead to synapse destabilization. Gong Y  Chang L  Viola K  Lacor P  Lambert M  Finch C  Krafft G  Klein W 

    Alternative statements
    

    • In 6 month old 3xTg-AD mice there is no apparent extracellular Aβ, suggesting that intraneuronal Aβ accumulation is most likely responsible for the deficits in LTP observed. Smith I  Green K  LaFerla F 
  • Soluble aggregates of Aβ, termed Aβ oligomers, may play a causative role in AD pathogenesis.

    SHOW Details   Supporting(7)   Consistent(1) 

    Experimental Approach: Animal models,   Pathophysiology,   Mechanism - biochemistry and structural biology,   Mechanism - molecular and cell
    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
    • Cheng I, Scearce-Levie K, Legleiter J, Palop J, Gerstein H, Bien-Ly N, Puoliväli J, Lesné S, Ashe K, Muchowski P, Mucke L
      Accelerating amyloid-beta fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models.
      The Journal of biological chemistry. 2007 Aug 17;282(33):23818-28
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Oddo S, Caccamo A, Shepherd J, Murphy M, Golde T, Kayed R, Metherate R, Mattson M, Akbari Y, LaFerla F
      Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction.
      Neuron. 2003 Jul 31;39(3):409-21
    • Cleary J, Walsh D, Hofmeister J, Shankar G, Kuskowski M, Selkoe D, Ashe K
      Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function.
      Nature neuroscience. 2005 Jan;8(1):79-84
    • Lesné S, Koh M, Kotilinek L, Kayed R, Glabe C, Yang A, Gallagher M, Ashe K
      A specific amyloid-beta protein assembly in the brain impairs memory.
      Nature. 2006 Mar 16;440(7082):352-7
    • 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
    

    • Aβ may give rise to small toxic derivatives other than the highly aggregated species found in amyloid deposits. 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 
  • Synthetic Aβ oligomers bind to differentiated hippocampal neurons at binding sites that colocalize with the synaptic marker PSD-95 suggesting that oligomers target synapses.

    SHOW Details   Supporting(3) 

    Description: These data would support the hypothesis that AD is in large part a synaptic pathology, and would be consistent with their rapid, selective inhibition of LTP.
    Experimental Approach: Mechanism - molecular and cell,   Mechanism - biochemistry and structural biology,   Biomarkers,   Pathophysiology,  
    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
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Selkoe D
      Alzheimer's disease is a synaptic failure.
      Science (New York, N.Y.). 2002 Oct 25;298(5594):789-91
  • Soluble Aβ levels correlate strongly with extent of synaptic loss and cognitive impairment.

    SHOW Details   Supporting(3)   Consistent(4)     Genes/Proteins: (1)

    Experimental Approach: Neuropsychology/Behavior,   Mechanism - biochemistry and structural biology,   Pathophysiology
    Pathogenic Narrative Tags: Pathologic change
    Supporting Evidence
    

    • McLean C, Cherny R, Fraser F, Fuller S, Smith M, Beyreuther K, Bush A, Masters C
      Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease.
      Annals of neurology. 1999 Dec;46(6):860-6
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Lue L, Kuo Y, Roher A, Brachova L, Shen Y, Sue L, Beach T, Kurth J, Rydel R, Rogers J
      Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease.
      The American journal of pathology. 1999 Sep;155(3):853-62

    Consistent statements
    

    • Synthetic Aβ aggregates, termed ADDLs, are highly toxic and inhibit hippocampal function. Wolozin B 
    • Soluble, diffusible Aβ oligomers can interrupt memory circuits in the brain. 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 
    • 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 

    Genes/Proteins
    

    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • Filamentous Aβ oligomers are not detected in conditioned media of transfected V717F APP751 cells.

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

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

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Genes/Proteins
    

    • Gene: APP amyloid beta (A4) precursor protein [Homo sapiens]
    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • Aβ oligomers inhibit long term potentiation in the hippocampus.

    SHOW Details   Supporting(1)   Consistent(5) 

    Description: Microinjection into living rats of culture medium containing naturally secreted human Aβ revealed that Aβ oligomers (in the absence of monomers and amyloid fibrils) can inhibit long-term potentiation in the hippocampus, which is required for memory formation.
    Experimental Approach: Mechanism - biochemistry and structural biology,   Pathophysiology,   Mechanism - physiological systems
    Pathogenic Narrative Tags: Pathogenic event
    Supporting Evidence
    

    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Consistent statements
    

    • LTP is a measure of synaptic plasticity that is disrupted by synthetic Aβ. Walsh D  Klyubin I  Fadeeva J  Cullen W  Anwyl R  Wolfe M  Rowan M  Selkoe D 
    • Soluble Aβ assemblies disrupt memory. Lesné S  Koh M  Kotilinek L  Kayed R  Glabe C  Yang A  Gallagher M  Ashe K 
    • Aβ oligomers applied to brain slices or injected in vivo cause failure of hippocampal LTP. Gong Y  Chang L  Viola K  Lacor P  Lambert M  Finch C  Krafft G  Klein W 
    • Conditioned media of V717F APP751 transfected cells depleted of monomeric Aβ blocked LTP, suggesting that naturally secreted soluble human Aβ oligomers are specifically responsible for the block of hippocampal LTP. Walsh D  Klyubin I  Fadeeva J  Cullen W  Anwyl R  Wolfe M  Rowan M  Selkoe D 
    • ADDLs block the reversal of LTD and formation of LTP, and may lead to synapse destabilization. Gong Y  Chang L  Viola K  Lacor P  Lambert M  Finch C  Krafft G  Klein W 
  • Fibrillar Aβ are neurotoxic in vitro.

    SHOW Details   Supporting(3)   Consistent(2)     Genes/Proteins: (1)

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

    • Lorenzo A, Yankner B
      Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red.
      Proceedings of the National Academy of Sciences of the United States of America. 1994 Dec 6;91(25):12243-7
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Pike C, Walencewicz A, Glabe C, Cotman C
      In vitro aging of beta-amyloid protein causes peptide aggregation and neurotoxicity.
      Brain research. 1991 Nov 1;563(1-2):311-4

    Consistent statements
    

    • Fibrillar Aβ kills cultured neurons. Gong Y  Chang L  Viola K  Lacor P  Lambert M  Finch C  Krafft G  Klein W 
    • In AD and other CNS proteinopathies some species of the aggregated misfolded protein are directly neurotoxic. Golde T  Miller V 

    Genes/Proteins
    

    • Protein: Amyloid beta A4 protein [Homo sapiens]
  • Conditioned media of V717F APP751 transfected cells depleted of monomeric Aβ blocked LTP, suggesting that naturally secreted soluble human Aβ oligomers are specifically responsible for the block of hippocampal LTP.

    SHOW Details   Supporting(2)   Consistent(7)   Inconsistent(1) 

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

    • Qiu W, Walsh D, Ye Z, Vekrellis K, Zhang J, Podlisny M, Rosner M, Safavi A, Hersh L, Selkoe D
      Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation.
      The Journal of biological chemistry. 1998 Dec 4;273(49):32730-8
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9

    Consistent statements
    

    • Various preparations of aggregated Aβ can inhibit LTP. Hartley D  Zhao C  Speier A  Woodard G  Li S  Li Z  Walz T 
    • A specific form of naturally secreted Aβ blocks long-term potentiation in the absence of monomers, protofibrils and fibrils, directly in living, anesthetized rats. Selkoe D 
    • Aβ oligomers applied to brain slices or injected in vivo cause failure of hippocampal LTP. Gong Y  Chang L  Viola K  Lacor P  Lambert M  Finch C  Krafft G  Klein W 
    • Aβ oligomers inhibit long term potentiation in the hippocampus. Hardy J  Selkoe D 
    • Aβ*56 has the ability to disrupt memory function directly and is the principal cause of memory decline. Lesné S  Koh M  Kotilinek L  Kayed R  Glabe C  Yang A  Gallagher M  Ashe K 
    • An additional study extends the finding that conditioned media depleted of Aβ monomers blocked LTP, by comparing the effect of size exclusion chromatography (SEC) separated monomer and oligomers, and by demonstrating that the effect can be blocked using mouse hippocampii. Walsh D 
    • ADDLs block the reversal of LTD and formation of LTP, and may lead to synapse destabilization. Gong Y  Chang L  Viola K  Lacor P  Lambert M  Finch C  Krafft G  Klein W 

    Inconsistent statements
    

    • In 6 month old 3xTg-AD mice there is no apparent extracellular Aβ, suggesting that intraneuronal Aβ accumulation is most likely responsible for the deficits in LTP observed. Smith I  Green K  LaFerla F 
  • Different from native Aβ42 dimers and cell-secreted or synthetic oligomers, which are neurotoxic, Aβ42 monomers are devoid of neurotoxicity in a number of different studies.

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

    Experimental Approach:
    Pathogenic Narrative Tags:
    Supporting Evidence
    

    • Klyubin I, Betts V, Welzel A, Blennow K, Zetterberg H, Wallin A, Lemere C, Cullen W, Peng Y, Wisniewski T, Selkoe D, Anwyl R, Walsh D, Rowan M
      Amyloid beta protein dimer-containing human CSF disrupts synaptic plasticity: prevention by systemic passive immunization.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2008 Apr 16;28(16):4231-7
    • 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
    • Walsh D, Klyubin I, Fadeeva J, Cullen W, Anwyl R, Wolfe M, Rowan M, Selkoe D
      Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
      Nature. 2002 Apr 4;416(6880):535-9
    • Shankar G, Li S, Mehta T, Garcia-Munoz A, Shepardson N, Smith I, Brett F, Farrell M, Rowan M, Lemere C, Regan C, Walsh D, Sabatini B, Selkoe D
      Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory.
      Nature medicine. 2008 Aug;14(8):837-42

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
• Created On: Wed, Apr 23 03:57:58 EDT 2008
• Last Modified On: Wed Apr 23 03:57:58 EDT 2008