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• A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease.
• Citation:
  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
  [PubMed] [Alzforum]
• Supporting:
  • 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]
  • 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
  • Hasegawa comment on Hardy hypothesis "A critical reappraisal of the Amyloid Hypothesis, in response to inconclusive clinical trial results."
    Hasegawa T Wed, Feb 10 2010 15:03:42 EST SHOW Details 
    This comment discusses John Hardy’s suggestion that recent clinical trials based on the amyloid hypothesis have been inconclusive. The author suggests that Alzheimer Disease pathogenic mechanisms may be different between human and mice. The response to drugs is often different between humans and AD mice. In addition, metabolism of toxic compounds can be different between species. These observations suggest that AD pathologic mechanisms may be different between species.

    Full text of comment:

    At present it has been known that the amyloid toxicity was dissociated from the cognitive impairment, that is, Alzheimer's treatment in amyloid toxicity was not consisted between mice and human experiment. Amyloid treatment induced the cognitive recovery in mice, but in human case, the same recovery could not be observed. In ICAD congress 2009, one report has attracted many attentions of scientist. The drug dimebon was approved to cure the cognitive impairment of Alzheimer's patient, which has been reported to increase beta-amyloid protein in Alzheimer's model mice. This unexpected result shows an inconsistent result between human and mice case. Why was the inconsistent result observed between human and mice case?

    We recently have observed the big difference of urinary excretion of homocysteic acid (HA) between human and mice. Here is main result. Comparison of urinary HA level between human and mice

    Human (male): 34 .8 + 8.1 m moles/70 kg body weight/day (n=7)

    Mice (male): 25.1+ 5.0 n moles/40 g body weight/day (n=5)

    [29.3 + 5.8 μmoles/70kg body weight/day]

    Human/mice = 1187

    Human: Male Down syndrome (36.1 + 5.3 years old)

    Mice: Male 3xTg-AD mice (12 month old)

    What do you think about this result? The result is simply compared at same body weight between human and mice. This method is not adequated to compare them, but urinary excretion of HA is easy compared between them. Now human excreted HA more than 1000 times higher than that of mice.This observation suggests that human is more severe for HA toxicity than mice. In other words, human pathogenic mechansim is quite different from that of mice.

    Now it is easy understood that Alzheimer's pathogenic mechanism seems to be different between human and mice case, then we should pay attention to use the model mice for the study of Alzheimer's pathogenic mechanism carefully.

    Additional cited evidence: Gandy et al 2009. Dimebon®, A Clinically Promising Drug For Alzheimer Disease, Regulates Amyloid-Beta Metabolism In Cultured Cells, In Isolated Nerve Terminals, And In The Interstitial Fluid Of The Living Rodent Brain. Jul 15, 2009 ICAD 2009. S4-04-06
    

    • Janus et al., 2000
    • Chwatko et al., 2007
    • Hasegawa et al., 2005
  • 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 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.

    SHOW Details   Supporting(1)   Consistent(3) 

    Description: In addition, active immunization had no effect on the total insoluble pool of Aβ in brain. The researchers concluded, however, that the prevention of memory deficits was due to the reduced amyloid pathology seen in their immunized mice.
    Experimental Approach: Animal models,   Target validation,   Pathophysiology,   Neuropsychology/Behavior
    Pathogenic Narrative Tags: Pathologic change
    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

    Consistent statements
    

    • 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. Holmes C  Boche D  Wilkinson D  Yadegarfar G  Hopkins V  Bayer A  Jones R  Bullock R  Love S  Neal J  Zotova E  Nicoll J 
    • Anti-Aβ vaccines can reduce the cognitive deficit associated with the accumulation of Aβ, without removing the neuritic plaques. Wolozin B 
    • 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. Dodart J  Bales K  Gannon K  Greene S  DeMattos R  Mathis C  DeLong C  Wu S  Wu X  Holtzman D  Paul S 
• 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 09:07:18 EDT 2008
• Last Modified On: Wed Apr 23 09:07:18 EDT 2008