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• A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease.
• Citation:
  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
  [PubMed] [Alzforum]
• Supporting:
  • 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]
  • The prediction that reducing Aβ and plaques would ameliorate Alzheimer symptoms and the observation that Aβ immunization immediately ameliorated the subtle behavioral alterations in transgenic APP animals, interpreted as indicating that this prediction had been fulfilled in animals, was perhaps premature.

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

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

    • Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P
      Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse.
      Nature. 1999 Jul 8;400(6740):173-7
    • Bard F, Cannon C, Barbour R, Burke R, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D, Yednock T
      Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease.
      Nature medicine. 2000 Aug;6(8):916-9
    • 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
    • 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

    Consistent statements
    

    • Amyloid toxicity is dissociated from cognitive impairment in AD patients. Hasegawa T 

    Genes/Proteins
    

    • Gene: APP amyloid beta (A4) precursor protein [Homo sapiens]
    • Protein: Beta-amyloid protein 42 [Homo sapiens]
  • Soluble Aβ oligomers have been implicated in age-dependent onset of memory failure in APP transgenic mice.

    SHOW Details   Supporting(4)   Consistent(2) 

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

    • Dodart J, Bales K, Gannon K, Greene S, DeMattos R, Mathis C, DeLong C, Wu S, Wu X, Holtzman D, Paul S
      Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model.
      Nature neuroscience. 2002 May;5(5):452-7
    • 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
    • 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
    • Kotilinek L, Bacskai B, Westerman M, Kawarabayashi T, Younkin L, Hyman B, Younkin S, Ashe K
      Reversible memory loss in a mouse transgenic model of Alzheimer's disease.
      The Journal of neuroscience : the official journal of the Society for Neuroscience. 2002 Aug 1;22(15):6331-5

    Consistent statements
    

    • Synthetic Aβ aggregates, termed ADDLs, are highly toxic and inhibit hippocampal function. Wolozin B 
    • ADDLs are potent neurotoxins to the principal neurons of the hippocampus (pyramidal and granule cells, respectively). 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 
  • Active immunization can prevent the development of AD-like neuropathology as well as preventing memory impairment in several mouse models of AD.

    SHOW Details   Supporting(4) 

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

    • Weiner H, Lemere C, Maron R, Spooner E, Grenfell T, Mori C, Issazadeh S, Hancock W, Selkoe D
      Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease.
      Annals of neurology. 2000 Oct;48(4):567-79
    • 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
    • Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P
      Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse.
      Nature. 1999 Jul 8;400(6740):173-7
    • 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
  • Both active and passive immunization against Aβ have recently been reported to prevent Aβ and amyloid deposition in transgenic mouse models of AD

    SHOW Details   Supporting(7)   Consistent(1)   Alternative to: (1)

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

    • 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
    • DeMattos R, Bales K, Cummins D, Dodart J, Paul S, Holtzman D
      Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease.
      Proceedings of the National Academy of Sciences of the United States of America. 2001 Jul 17;98(15):8850-5
    • Weiner H, Lemere C, Maron R, Spooner E, Grenfell T, Mori C, Issazadeh S, Hancock W, Selkoe D
      Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease.
      Annals of neurology. 2000 Oct;48(4):567-79
    • 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
    • Sigurdsson E, Scholtzova H, Mehta P, Frangione B, Wisniewski T
      Immunization with a nontoxic/nonfibrillar amyloid-beta homologous peptide reduces Alzheimer's disease-associated pathology in transgenic mice.
      The American journal of pathology. 2001 Aug;159(2):439-47
    • Bard F, Cannon C, Barbour R, Burke R, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D, Yednock T
      Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease.
      Nature medicine. 2000 Aug;6(8):916-9
    • Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P
      Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse.
      Nature. 1999 Jul 8;400(6740):173-7

    Consistent statements
    

    • ADDLs-specific antibodies may safely preserve or restore memory functions in human AD. Gong Y  Chang L  Viola K  Lacor P  Lambert M  Finch C  Krafft G  Klein W 

    Alternative statements
    

    • Anti-Aβ vaccines can reduce the cognitive deficit associated with the accumulation of Aβ, without removing the neuritic plaques. Wolozin B 
  • 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]
  • Active immunization of mice genetically modified to develop Aβ plaques as they age with full-length Aβ (Aβ42) resulted in a reduction of plaque burden and improved cognitive function.

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

    Experimental Approach: Mechanism - molecular and cell,   Animal models,   Pathophysiology,   Genetics,   Target validation
    Pathogenic Narrative Tags: Perturbation
    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
    • Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P
      Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse.
      Nature. 1999 Jul 8;400(6740):173-7

    Consistent statements
    

    • Strong support for the hypothesis that Aβ is the initial trigger of Alzheimer Disease comes from human genetic data although recent advances in transgenic models have also provided critical corroborating evidence. Smith I  Green K  LaFerla F 
    • Active immunization with Aβ of mutant APP TgCRND8 mice partially prevented the development of reference memory deficits in a water maze task with only a 50% reduction in the size and number of dense core amyloid deposits. Dodart J  Bales K  Gannon K  Greene S  DeMattos R  Mathis C  DeLong C  Wu S  Wu X  Holtzman D  Paul S 

    Genes/Proteins
    

    • Protein: Beta-amyloid protein 42 [Homo sapiens]
  • Chronic active immunization had beneficial effects on memory impairment in two different strains of transgenic mice as assessed using a radial-arm water maze; but notably, treatment did not affect amyloid pathology in the same way in the two strains of mice.

    SHOW Details   Supporting(1) 

    Description: Immunized Tg2576 APP+PS1 double transgenic mice showed a reduction in diffuse (nonfibrillar) Aβ deposits in the cerebral cortex and hippocampus, but not in amyloid (fibrillar Aβ) deposits. In contrast, Tg2576 APP transgenic mice showed a small but statistically significant reduction in cortical amyloid burden, suggesting that active immunization reduces the development of fibrillar Aβ deposits in this mouse strain. These authors concluded that active immunization prevents memory deficits by altering either brain amyloid pathology or an unknown pool of non-deposited Aβ, perhaps a soluble pool of Aβ.
    Experimental Approach: Neuropsychology/Behavior,   Pathophysiology,   Target validation,   Animal models
    Pathogenic Narrative Tags: Pathologic change
    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
• Discussed by:
  Previous studies have suggested that the reduction in cognitive impairment seen in APP transgenic mice after active immunization requires reduced brain Aβ/amyloid burden, but m266 treatment of PDAPP mice appears to contradict these findings.
  SHOW Details   Discussing: (4)  Consistent(2) 
  Experimental Approach: Target validation,   Pathophysiology,   Neuropsychology/Behavior,   Animal models
  Pathogenic Narrative Tags: Pathologic change
  Discussing 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
  • Weiner H, Lemere C, Maron R, Spooner E, Grenfell T, Mori C, Issazadeh S, Hancock W, Selkoe D
    Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease.
    Annals of neurology. 2000 Oct;48(4):567-79
  • Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P
    Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse.
    Nature. 1999 Jul 8;400(6740):173-7
  • 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
  Consistent statements
  
  • Active immunization with Aβ of mutant APP TgCRND8 mice partially prevented the development of reference memory deficits in a water maze task with only a 50% reduction in the size and number of dense core amyloid deposits. Dodart J  Bales K  Gannon K  Greene S  DeMattos R  Mathis C  DeLong C  Wu S  Wu X  Holtzman D  Paul S 
  • Anti-Aβ vaccines can reduce the cognitive deficit associated with the accumulation of Aβ, without removing the neuritic plaques. Wolozin B 
• Created On: Wed, Apr 23 04:47:05 EDT 2008
• Last Modified On: Wed Apr 23 04:47:05 EDT 2008