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BIOMD0000000488 - Proctor2013 - Effect of Aβ immunisation in Alzheimer's disease

 

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Reference Publication
Publication ID: 24098635
Proctor CJ, Boche D, Gray DA, Nicoll JA.
Investigating interventions in Alzheimer's disease with computer simulation models.
PLoS ONE 2013; 8(9): e73631
Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom.  [more]
Model
Original Model: Proctor2012_GSK3_p53_Alzhe...
Submitter: Carole Proctor
Submission ID: MODEL1212030000
Submission Date: 03 Dec 2012 09:44:56 UTC
Last Modification Date: 29 Sep 2014 14:48:59 UTC
Creation Date: 24 Sep 2013 11:45:36 UTC
Encoders:  Vijayalakshmi Chelliah
   Carole Proctor
set #1
bqmodel:isDerivedFrom BioModels Database Proctor2010 - a link between GSK3 and p53 in Alzheimer's disease
BioModels Database Proctor2012 - Role of Amyloid-beta dimers in aggregation formation
set #2
bqbiol:isVersionOf Gene Ontology DNA damage response, signal transduction by p53 class mediator
Gene Ontology inclusion body assembly
set #3
bqbiol:isPartOf Pathway Ontology Alzheimer disease pathway
bqbiol:hasTaxon Taxonomy Mammalia
set #4
bqbiol:hasProperty Mathematical Modelling Ontology MAMO_0000046
set #5
bqbiol:hasVersion Human Disease Ontology Alzheimer's disease
Notes
Proctor2013 - Effect of Aβ immunisation in Alzheimer's disease

Extension of a previously published stochastic computer model (designed to examine some of the key pathways involved in the aggregation of amyloid-beta (Aβ) and the micro-tubular binding protein tau) to include the main processes involved in passive and active immunisation against Aβ and then demonstrate the effects of this intervention on soluble Aβ.

This model is described in the article:

Proctor CJ, Boche D, Gray DA, Nicoll JA
PLoS ONE 2013; 8(9): e73631

Abstract:

Progress in the development of therapeutic interventions to treat or slow the progression of Alzheimer's disease has been hampered by lack of efficacy and unforeseen side effects in human clinical trials. This setback highlights the need for new approaches for pre-clinical testing of possible interventions. Systems modelling is becoming increasingly recognised as a valuable tool for investigating molecular and cellular mechanisms involved in ageing and age-related diseases. However, there is still a lack of awareness of modelling approaches in many areas of biomedical research. We previously developed a stochastic computer model to examine some of the key pathways involved in the aggregation of amyloid-beta (Aβ) and the micro-tubular binding protein tau. Here we show how we extended this model to include the main processes involved in passive and active immunisation against Aβ and then demonstrate the effects of this intervention on soluble Aβ, plaques, phosphorylated tau and tangles. The model predicts that immunisation leads to clearance of plaques but only results in small reductions in levels of soluble Aβ, phosphorylated tau and tangles. The behaviour of this model is supported by neuropathological observations in Alzheimer patients immunised against Aβ. Since, soluble Aβ, phosphorylated tau and tangles more closely correlate with cognitive decline than plaques, our model suggests that immunotherapy against Aβ may not be effective unless it is performed very early in the disease process or combined with other therapies.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Model
Publication ID: 24098635 Submission Date: 03 Dec 2012 09:44:56 UTC Last Modification Date: 29 Sep 2014 14:48:59 UTC Creation Date: 24 Sep 2013 11:45:36 UTC
Mathematical expressions
Reactions
p53mRNASynthesis p53mRNADegradation Mdm2Synthesis Mdm2mRNASynthesis1
Mdm2mRNASynthesis2 Mdm2mRNASynthesis3 Mdm2mRNASynthesis4 Mdm2mRNADegradation
P53Mdm2Binding P53Mdm2Release GSK3p53Binding GSK3p53Release
GSK3p53PBinding GSK3_p53PRelease E1UbBinding E2UbBinding
Mdm2Ubiquitination Mdm2polyUbiquitination1 Mdm2polyUbiquitination2 Mdm2polyUbiquitination3
Mdm2Deubiquitination4 Mdm2Deubiquitination3 Mdm2Deubiquitination2 Mdm2Deubiquitination1
Mdm2ProteasomeBinding1 Mdm2Degradation p53Synthesis p53Monoubiquitination
p53Polyubiquitination1 p53Polyubiquitination2 p53Polyubiquitination3 p53Deubiqutination4
p53Deubiquitination3 p53Deubiquitination2 p53Deubiquitination1 Mdm2GSK3phosphorylation1
Mdm2GSK3phosphorylation2 Mdm2GSK3phosphorylation3 p53ProteasomeBinding1 Degradationp53_Ub4
TauMTbinding TauMTrelease Tauphosphorylation1 Tauphosphorylation2
Tauphosphorylation3 Tauphosphorylation4 Tauphosphorylation5 Tauphosphorylation6
Taudephosphorylation1 Taudephosphorylation2 TauP1Aggregation1 TauP1Aggregation2
TauP2Aggregation1 TauP2Aggregation2 TauAggregation1 TauAggregation2
TangleFormation1 TangleFormation2 ProteasomeInhibitionAggTau Abetaproduction1
Abetaproduction2 Abetaproduction3 ProteasomeInhibitionAbeta AbetaDegradation
p53transcriptionViaAbeta DNAdamage DNArepair ATMactivation
p53phosphorylation p53dephosphorylation Mdm2phosphorylation Mdm2dephosphorylation
Mdm2PUbiquitination Mdm2PpolyUbiquitination1 Mdm2PpolyUbiquitination2 Mdm2PpolyUbiquitination3
Mdm2PDeubiquitination4 Mdm2PDeubiquitination3 Mdm2PDeubiquitination2 Mdm2PDeubiquitination1
Mdm2PProteasomeBinding1 Mdm2PDegradation ATMInactivation AbetaROSproduction1
PlaqueROSproduction AggAbetaROSproduction2 ROSDNAdamage TauSynthesis
TauProteasomeBinding Tau20SProteasomeDegradation AbetaAggregation1 AbetaPlaqueFormation1
AbetaPlaqueGrowth AbetaDisaggregation1 AbetaDisaggregation3 AbetaDisaggregation4
Abeta_antiAbBinding AbetaDimer_antiAbBinding Abeta_antiAbDegredation AbetaDimer_antiAbDegredation
GliaActivationStep1 GliaActivationStep2 GliaActivationStep3 GliaInactivationStep1
GliaInactivationStep2 GliaInactivationStep3 AbetaBindingToGlia AbetaReleaseFromGlia
AbetaPlaqueClearanceByGlia ROSgenerationByGlia antiAbRemoval ROSremoval
Events
ImmunizeCell      
Physical entities
Compartments Species
cell Mdm2 p53 Mdm2_p53
Mdm2_mRNA p53_mRNA ATMA
ATMI p53_P Mdm2_P
IR ROS damDNA
E1 E2 E1_Ub
E2_Ub Proteasome Ub
p53DUB Mdm2DUB DUB
Mdm2_p53_Ub Mdm2_p53_Ub2 Mdm2_p53_Ub3
Mdm2_p53_Ub4 Mdm2_P1_p53_Ub4 Mdm2_Ub
Mdm2_Ub2 Mdm2_Ub3 Mdm2_Ub4
Mdm2_P_Ub Mdm2_P_Ub2 Mdm2_P_Ub3
Mdm2_P_Ub4 p53_Ub4_Proteasome Mdm2_Ub4_Proteasome
Mdm2_P_Ub4_Proteasome GSK3b GSK3b_p53
GSK3b_p53_P Abeta AggAbeta_Proteasome
AbetaPlaque Tau Tau_P1
Tau_P2 MT_Tau AggTau
AggTau_Proteasome Proteasome_Tau PP1
NFT ATP ADP
AMP AbetaDimer AbetaPlaque_GliaA
GliaI GliaM1 GliaM2
GliaA antiAb Abeta_antiAb
AbetaDimer_antiAb degAbetaGlia disaggPlaque1
disaggPlaque2 Source Sink
Global parameters
ksynp53mRNA kdegp53mRNA ksynMdm2mRNA kdegMdm2mRNA
ksynMdm2mRNAGSK3bp53 ksynp53 kdegp53 kbinMdm2p53
krelMdm2p53 kbinGSK3bp53 krelGSK3bp53 ksynMdm2
kdegMdm2 kbinE1Ub kbinE2Ub kp53Ub
kp53PolyUb kbinProt kactDUBp53 kactDUBProtp53
kactDUBMdm2 kMdm2Ub kMdm2PUb kMdm2PolyUb
kdam krepair kactATM kinactATM
kphosp53 kdephosp53 kphosMdm2 kdephosMdm2
kphosMdm2GSK3b kphosMdm2GSK3bp53 kphospTauGSK3bp53 kphospTauGSK3b
kdephospTau kbinMTTau krelMTTau ksynTau
kbinTauProt kdegTau20SProt kaggTau kaggTauP1
kaggTauP2 ktangfor kinhibprot ksynp53mRNAAbeta
kdamROS kgenROSAbeta kgenROSPlaque kgenROSGlia
kproteff kremROS kprodAbeta kprodAbeta2
kdegAbeta kaggAbeta kdisaggAbeta kdisaggAbeta1
kdisaggAbeta2 kdegAbetaGlia kpf kpg
kpghalf kactglia1 kactglia2 kinactglia1
kinactglia2 kbinAbetaGlia krelAbetaGlia kdegAntiAb
kbinAbantiAb      
Reactions (112)
 
 p53mRNASynthesis [Source] → [p53_mRNA];   {Source}
 
 p53mRNADegradation [p53_mRNA] → [Sink];   {p53_mRNA}
 
 Mdm2Synthesis [Mdm2_mRNA] → [Mdm2_mRNA] + [Mdm2];   {Mdm2_mRNA}
 
 Mdm2mRNASynthesis1 [p53] → [p53] + [Mdm2_mRNA];   {p53}
 
 Mdm2mRNASynthesis2 [p53_P] → [p53_P] + [Mdm2_mRNA];   {p53_P}
 
 Mdm2mRNASynthesis3 [GSK3b_p53] → [GSK3b_p53] + [Mdm2_mRNA];   {GSK3b_p53}
 
 Mdm2mRNASynthesis4 [GSK3b_p53_P] → [GSK3b_p53_P] + [Mdm2_mRNA];   {GSK3b_p53_P}
 
 Mdm2mRNADegradation [Mdm2_mRNA] → [Sink];   {Mdm2_mRNA}
 
 P53Mdm2Binding [p53] + [Mdm2] → [Mdm2_p53];   {p53} , {Mdm2}
 
 P53Mdm2Release [Mdm2_p53] → [p53] + [Mdm2];   {Mdm2_p53}
 
 GSK3p53Binding [GSK3b] + [p53] → [GSK3b_p53];   {GSK3b} , {p53}
 
 GSK3p53Release [GSK3b_p53] → [GSK3b] + [p53];   {GSK3b_p53}
 
 GSK3p53PBinding [GSK3b] + [p53_P] → [GSK3b_p53_P];   {GSK3b} , {p53_P}
 
 GSK3_p53PRelease [GSK3b_p53_P] → [GSK3b] + [p53_P];   {GSK3b_p53_P}
 
 E1UbBinding [E1] + [Ub] + [ATP] → [E1_Ub] + [AMP];   {E1} , {Ub} , {ATP}
 
 E2UbBinding [E2] + [E1_Ub] → [E2_Ub] + [E1];   {E2} , {E1_Ub}
 
 Mdm2Ubiquitination [Mdm2] + [E2_Ub] → [Mdm2_Ub] + [E2];   {Mdm2} , {E2_Ub}
 
 Mdm2polyUbiquitination1 [Mdm2_Ub] + [E2_Ub] → [Mdm2_Ub2] + [E2];   {Mdm2_Ub} , {E2_Ub}
 
 Mdm2polyUbiquitination2 [Mdm2_Ub2] + [E2_Ub] → [Mdm2_Ub3] + [E2];   {Mdm2_Ub2} , {E2_Ub}
 
 Mdm2polyUbiquitination3 [Mdm2_Ub3] + [E2_Ub] → [Mdm2_Ub4] + [E2];   {Mdm2_Ub3} , {E2_Ub}
 
 Mdm2Deubiquitination4 [Mdm2_Ub4] + [Mdm2DUB] → [Mdm2_Ub3] + [Mdm2DUB] + [Ub];   {Mdm2_Ub4} , {Mdm2DUB}
 
 Mdm2Deubiquitination3 [Mdm2_Ub3] + [Mdm2DUB] → [Mdm2_Ub2] + [Mdm2DUB] + [Ub];   {Mdm2_Ub3} , {Mdm2DUB}
 
 Mdm2Deubiquitination2 [Mdm2_Ub2] + [Mdm2DUB] → [Mdm2_Ub] + [Mdm2DUB] + [Ub];   {Mdm2_Ub2} , {Mdm2DUB}
 
 Mdm2Deubiquitination1 [Mdm2_Ub] + [Mdm2DUB] → [Mdm2] + [Mdm2DUB] + [Ub];   {Mdm2_Ub} , {Mdm2DUB}
 
 Mdm2ProteasomeBinding1 [Mdm2_Ub4] + [Proteasome] → [Mdm2_Ub4_Proteasome];   {Mdm2_Ub4} , {Proteasome}
 
 Mdm2Degradation [Mdm2_Ub4_Proteasome] → [Proteasome] + 4.0 × [Ub];   {Mdm2_Ub4_Proteasome}
 
 p53Synthesis [p53_mRNA] → [p53] + [p53_mRNA];   {p53_mRNA}
 
 p53Monoubiquitination [E2_Ub] + [Mdm2_p53] → [Mdm2_p53_Ub] + [E2];   {E2_Ub} , {Mdm2_p53}
 
 p53Polyubiquitination1 [Mdm2_p53_Ub] + [E2_Ub] → [Mdm2_p53_Ub2] + [E2];   {Mdm2_p53_Ub} , {E2_Ub}
 
 p53Polyubiquitination2 [Mdm2_p53_Ub2] + [E2_Ub] → [Mdm2_p53_Ub3] + [E2];   {Mdm2_p53_Ub2} , {E2_Ub}
 
 p53Polyubiquitination3 [Mdm2_p53_Ub3] + [E2_Ub] → [Mdm2_p53_Ub4] + [E2];   {Mdm2_p53_Ub3} , {E2_Ub}
 
 p53Deubiqutination4 [Mdm2_p53_Ub4] + [p53DUB] → [Mdm2_p53_Ub3] + [p53DUB] + [Ub];   {Mdm2_p53_Ub4} , {p53DUB}
 
 p53Deubiquitination3 [Mdm2_p53_Ub3] + [p53DUB] → [Mdm2_p53_Ub2] + [p53DUB] + [Ub];   {Mdm2_p53_Ub3} , {p53DUB}
 
 p53Deubiquitination2 [Mdm2_p53_Ub2] + [p53DUB] → [Mdm2_p53_Ub] + [p53DUB] + [Ub];   {Mdm2_p53_Ub2} , {p53DUB}
 
 p53Deubiquitination1 [Mdm2_p53_Ub] + [p53DUB] → [Mdm2_p53] + [p53DUB] + [Ub];   {Mdm2_p53_Ub} , {p53DUB}
 
 Mdm2GSK3phosphorylation1 [Mdm2_p53_Ub4] + [GSK3b] → [Mdm2_P1_p53_Ub4] + [GSK3b];   {Mdm2_p53_Ub4} , {GSK3b}
 
 Mdm2GSK3phosphorylation2 [Mdm2_p53_Ub4] + [GSK3b_p53] → [Mdm2_P1_p53_Ub4] + [GSK3b_p53];   {Mdm2_p53_Ub4} , {GSK3b_p53}
 
 Mdm2GSK3phosphorylation3 [Mdm2_p53_Ub4] + [GSK3b_p53_P] → [Mdm2_P1_p53_Ub4] + [GSK3b_p53_P];   {Mdm2_p53_Ub4} , {GSK3b_p53_P}
 
 p53ProteasomeBinding1 [Mdm2_P1_p53_Ub4] + [Proteasome] → [p53_Ub4_Proteasome] + [Mdm2];   {Mdm2_P1_p53_Ub4} , {Proteasome}
 
 Degradationp53_Ub4 [p53_Ub4_Proteasome] + [ATP] → 4.0 × [Ub] + [Proteasome] + [ADP];   {p53_Ub4_Proteasome} , {ATP}
 
 TauMTbinding [Tau] → [MT_Tau];   {Tau}
 
 TauMTrelease [MT_Tau] → [Tau];   {MT_Tau}
 
 Tauphosphorylation1 [GSK3b_p53] + [Tau] → [GSK3b_p53] + [Tau_P1];   {GSK3b_p53} , {Tau}
 
 Tauphosphorylation2 [GSK3b_p53] + [Tau_P1] → [GSK3b_p53] + [Tau_P2];   {GSK3b_p53} , {Tau_P1}
 
 Tauphosphorylation3 [GSK3b_p53_P] + [Tau] → [GSK3b_p53_P] + [Tau_P1];   {GSK3b_p53_P} , {Tau}
 
 Tauphosphorylation4 [GSK3b_p53_P] + [Tau_P1] → [GSK3b_p53_P] + [Tau_P2];   {GSK3b_p53_P} , {Tau_P1}
 
 Tauphosphorylation5 [GSK3b] + [Tau] → [GSK3b] + [Tau_P1];   {GSK3b} , {Tau}
 
 Tauphosphorylation6 [GSK3b] + [Tau_P1] → [GSK3b] + [Tau_P2];   {GSK3b} , {Tau_P1}
 
 Taudephosphorylation1 [Tau_P2] + [PP1] → [Tau_P1] + [PP1];   {Tau_P2} , {PP1}
 
 Taudephosphorylation2 [Tau_P1] + [PP1] → [Tau] + [PP1];   {Tau_P1} , {PP1}
 
 TauP1Aggregation1 2.0 × [Tau_P1] → 2.0 × [AggTau];   {Tau_P1}
 
 TauP1Aggregation2 [Tau_P1] + [AggTau] → 2.0 × [AggTau];   {Tau_P1} , {AggTau}
 
 TauP2Aggregation1 2.0 × [Tau_P2] → 2.0 × [AggTau];   {Tau_P2}
 
 TauP2Aggregation2 [Tau_P2] + [AggTau] → 2.0 × [AggTau];   {Tau_P2} , {AggTau}
 
 TauAggregation1 2.0 × [Tau] → 2.0 × [AggTau];   {Tau}
 
 TauAggregation2 [Tau] + [AggTau] → 2.0 × [AggTau];   {Tau} , {AggTau}
 
 TangleFormation1 2.0 × [AggTau] → 2.0 × [NFT];   {AggTau}
 
 TangleFormation2 [AggTau] + [NFT] → 2.0 × [NFT];   {AggTau} , {NFT}
 
 ProteasomeInhibitionAggTau [AggTau] + [Proteasome] → [AggTau_Proteasome];   {AggTau} , {Proteasome}
 
 Abetaproduction1 [Source] → [Abeta];   {Source}
 
 Abetaproduction2 [GSK3b_p53] → [Abeta] + [GSK3b_p53];   {GSK3b_p53}
 
 Abetaproduction3 [GSK3b_p53_P] → [Abeta] + [GSK3b_p53_P];   {GSK3b_p53_P}
 
 ProteasomeInhibitionAbeta [AbetaDimer] + [Proteasome] → [AggAbeta_Proteasome];   {AbetaDimer} , {Proteasome}
 
 AbetaDegradation [Abeta] → [Sink];   {Abeta}
 
 p53transcriptionViaAbeta [Abeta] → [p53_mRNA] + [Abeta];   {Abeta}
 
 DNAdamage [IR] → [IR] + [damDNA];   {IR}
 
 DNArepair [damDNA] → [Sink];   {damDNA}
 
 ATMactivation [damDNA] + [ATMI] → [damDNA] + [ATMA];   {damDNA} , {ATMI}
 
 p53phosphorylation [p53] + [ATMA] → [p53_P] + [ATMA];   {p53} , {ATMA}
 
 p53dephosphorylation [p53_P] → [p53];   {p53_P}
 
 Mdm2phosphorylation [Mdm2] + [ATMA] → [Mdm2_P] + [ATMA];   {Mdm2} , {ATMA}
 
 Mdm2dephosphorylation [Mdm2_P] → [Mdm2];   {Mdm2_P}
 
 Mdm2PUbiquitination [Mdm2_P] + [E2_Ub] → [Mdm2_P_Ub] + [E2];   {Mdm2_P} , {E2_Ub}
 
 Mdm2PpolyUbiquitination1 [Mdm2_P_Ub] + [E2_Ub] → [Mdm2_P_Ub2] + [E2];   {Mdm2_P_Ub} , {E2_Ub}
 
 Mdm2PpolyUbiquitination2 [Mdm2_P_Ub2] + [E2_Ub] → [Mdm2_P_Ub3] + [E2];   {Mdm2_P_Ub2} , {E2_Ub}
 
 Mdm2PpolyUbiquitination3 [Mdm2_P_Ub3] + [E2_Ub] → [Mdm2_P_Ub4] + [E2];   {Mdm2_P_Ub3} , {E2_Ub}
 
 Mdm2PDeubiquitination4 [Mdm2_P_Ub4] + [Mdm2DUB] → [Mdm2_P_Ub3] + [Mdm2DUB] + [Ub];   {Mdm2_P_Ub4} , {Mdm2DUB}
 
 Mdm2PDeubiquitination3 [Mdm2_P_Ub3] + [Mdm2DUB] → [Mdm2_P_Ub2] + [Mdm2DUB] + [Ub];   {Mdm2_P_Ub3} , {Mdm2DUB}
 
 Mdm2PDeubiquitination2 [Mdm2_P_Ub2] + [Mdm2DUB] → [Mdm2_P_Ub] + [Mdm2DUB] + [Ub];   {Mdm2_P_Ub2} , {Mdm2DUB}
 
 Mdm2PDeubiquitination1 [Mdm2_P_Ub] + [Mdm2DUB] → [Mdm2_P] + [Mdm2DUB] + [Ub];   {Mdm2_P_Ub} , {Mdm2DUB}
 
 Mdm2PProteasomeBinding1 [Mdm2_P_Ub4] + [Proteasome] → [Mdm2_P_Ub4_Proteasome];   {Mdm2_P_Ub4} , {Proteasome}
 
 Mdm2PDegradation [Mdm2_P_Ub4_Proteasome] → [Proteasome] + 4.0 × [Ub];   {Mdm2_P_Ub4_Proteasome}
 
 ATMInactivation [ATMA] → [ATMI];   {ATMA}
 
 AbetaROSproduction1 [Abeta] → [Abeta] + [ROS];   {Abeta}
 
 PlaqueROSproduction [AbetaPlaque] → [AbetaPlaque] + [ROS];   {AbetaPlaque}
 
 AggAbetaROSproduction2 [AggAbeta_Proteasome] → [AggAbeta_Proteasome] + [ROS];   {AggAbeta_Proteasome}
 
 ROSDNAdamage [ROS] → [ROS] + [damDNA];   {ROS}
 
 TauSynthesis [Source] → [Tau];   {Source}
 
 TauProteasomeBinding [Tau] + [Proteasome] → [Proteasome_Tau];   {Tau} , {Proteasome}
 
 Tau20SProteasomeDegradation [Proteasome_Tau] → [Proteasome];   {Proteasome_Tau}
 
 AbetaAggregation1 2.0 × [Abeta] → [AbetaDimer];   {Abeta}
 
 AbetaPlaqueFormation1 2.0 × [AbetaDimer] → [AbetaPlaque];   {AbetaDimer}
 
 AbetaPlaqueGrowth [AbetaDimer] + [AbetaPlaque] → 2.0 × [AbetaPlaque];   {AbetaDimer} , {AbetaPlaque}
 
 AbetaDisaggregation1 [AbetaDimer] → 2.0 × [Abeta];   {AbetaDimer}
 
 AbetaDisaggregation3 [AbetaPlaque] → [AbetaDimer] + [disaggPlaque1];   {AbetaPlaque}
 
 AbetaDisaggregation4 [AbetaPlaque] + [antiAb] → [AbetaDimer] + [antiAb] + [disaggPlaque2];   {antiAb} , {AbetaPlaque}
 
 Abeta_antiAbBinding [Abeta] + [antiAb] → [Abeta_antiAb];   {Abeta} , {antiAb}
 
 AbetaDimer_antiAbBinding [AbetaDimer] + [antiAb] → [AbetaDimer_antiAb];   {AbetaDimer} , {antiAb}
 
 Abeta_antiAbDegredation [Abeta_antiAb] → [antiAb];   {Abeta_antiAb}
 
 AbetaDimer_antiAbDegredation [AbetaDimer_antiAb] → [antiAb];   {AbetaDimer_antiAb}
 
 GliaActivationStep1 [GliaI] + [AbetaPlaque] → [GliaM1] + [AbetaPlaque];   {GliaI} , {AbetaPlaque}
 
 GliaActivationStep2 [GliaM1] + [AbetaPlaque] → [GliaM2] + [AbetaPlaque];   {GliaM1} , {AbetaPlaque}
 
 GliaActivationStep3 [GliaM2] + [antiAb] → [GliaA] + [antiAb];   {GliaM2} , {antiAb}
 
 GliaInactivationStep1 [GliaA] → [GliaM2];   {GliaA}
 
 GliaInactivationStep2 [GliaM2] → [GliaM1];   {GliaM2}
 
 GliaInactivationStep3 [GliaM1] → [GliaI];   {GliaM1}
 
 AbetaBindingToGlia [AbetaPlaque] + [GliaA] → [AbetaPlaque_GliaA];   {AbetaPlaque} , {GliaA}
 
 AbetaReleaseFromGlia [AbetaPlaque_GliaA] → [AbetaPlaque] + [GliaA];   {AbetaPlaque_GliaA}
 
 AbetaPlaqueClearanceByGlia [AbetaPlaque_GliaA] → [GliaA] + [degAbetaGlia];   {AbetaPlaque_GliaA}
 
 ROSgenerationByGlia [AbetaPlaque_GliaA] → [AbetaPlaque_GliaA] + [ROS];   {AbetaPlaque_GliaA}
 
 antiAbRemoval [antiAb] → [Sink];   {antiAb}
 
 ROSremoval [ROS] → [Sink];   {ROS}
 
Events (1)
 
 ImmunizeCell
antiAb = 50
 
  Spatial dimensions: 3.0  Compartment size: 1.0
 
 Mdm2
Compartment: cell
Initial amount: 5.0
 
 p53
Compartment: cell
Initial amount: 5.0
 
 Mdm2_p53
Compartment: cell
Initial amount: 95.0
 
 Mdm2_mRNA
Compartment: cell
Initial amount: 10.0
 
 p53_mRNA
Compartment: cell
Initial amount: 10.0
 
 ATMA
Compartment: cell
Initial amount: 0.0
 
 ATMI
Compartment: cell
Initial amount: 200.0
 
 p53_P
Compartment: cell
Initial amount: 0.0
 
 Mdm2_P
Compartment: cell
Initial amount: 0.0
 
   IR
Compartment: cell
Initial amount: 0.0
 
 ROS
Compartment: cell
Initial amount: 0.0
 
 damDNA
Compartment: cell
Initial amount: 0.0
 
 E1
Compartment: cell
Initial amount: 100.0
 
 E2
Compartment: cell
Initial amount: 100.0
 
 E1_Ub
Compartment: cell
Initial amount: 0.0
 
 E2_Ub
Compartment: cell
Initial amount: 0.0
 
 Proteasome
Compartment: cell
Initial amount: 500.0
 
 Ub
Compartment: cell
Initial amount: 4000.0
 
 p53DUB
Compartment: cell
Initial amount: 200.0
 
 Mdm2DUB
Compartment: cell
Initial amount: 200.0
 
 DUB
Compartment: cell
Initial amount: 200.0
 
 Mdm2_p53_Ub
Compartment: cell
Initial amount: 0.0
 
 Mdm2_p53_Ub2
Compartment: cell
Initial amount: 0.0
 
 Mdm2_p53_Ub3
Compartment: cell
Initial amount: 0.0
 
 Mdm2_p53_Ub4
Compartment: cell
Initial amount: 0.0
 
 Mdm2_P1_p53_Ub4
Compartment: cell
Initial amount: 0.0
 
 Mdm2_Ub
Compartment: cell
Initial amount: 0.0
 
 Mdm2_Ub2
Compartment: cell
Initial amount: 0.0
 
 Mdm2_Ub3
Compartment: cell
Initial amount: 0.0
 
 Mdm2_Ub4
Compartment: cell
Initial amount: 0.0
 
 Mdm2_P_Ub
Compartment: cell
Initial amount: 0.0
 
 Mdm2_P_Ub2
Compartment: cell
Initial amount: 0.0
 
 Mdm2_P_Ub3
Compartment: cell
Initial amount: 0.0
 
 Mdm2_P_Ub4
Compartment: cell
Initial amount: 0.0
 
 p53_Ub4_Proteasome
Compartment: cell
Initial amount: 0.0
 
 Mdm2_Ub4_Proteasome
Compartment: cell
Initial amount: 0.0
 
 Mdm2_P_Ub4_Proteasome
Compartment: cell
Initial amount: 0.0
 
 GSK3b
Compartment: cell
Initial amount: 500.0
 
 GSK3b_p53
Compartment: cell
Initial amount: 0.0
 
 GSK3b_p53_P
Compartment: cell
Initial amount: 0.0
 
 Abeta
Compartment: cell
Initial amount: 0.0
 
 AggAbeta_Proteasome
Compartment: cell
Initial amount: 0.0
 
 AbetaPlaque
Compartment: cell
Initial amount: 0.0
 
 Tau
Compartment: cell
Initial amount: 0.0
 
 Tau_P1
Compartment: cell
Initial amount: 0.0
 
 Tau_P2
Compartment: cell
Initial amount: 0.0
 
 MT_Tau
Compartment: cell
Initial amount: 100.0
 
 AggTau
Compartment: cell
Initial amount: 0.0
 
 AggTau_Proteasome
Compartment: cell
Initial amount: 0.0
 
 Proteasome_Tau
Compartment: cell
Initial amount: 0.0
 
 PP1
Compartment: cell
Initial amount: 50.0
 
 NFT
Compartment: cell
Initial amount: 0.0
 
 ATP
Compartment: cell
Initial amount: 10000.0
Constant
 
 ADP
Compartment: cell
Initial amount: 1000.0
Constant
 
 AMP
Compartment: cell
Initial amount: 1000.0
Constant
 
 AbetaDimer
Compartment: cell
Initial amount: 0.0
 
 AbetaPlaque_GliaA
Compartment: cell
Initial amount: 0.0
 
 GliaI
Compartment: cell
Initial amount: 100.0
 
 GliaM1
Compartment: cell
Initial amount: 0.0
 
 GliaM2
Compartment: cell
Initial amount: 0.0
 
 GliaA
Compartment: cell
Initial amount: 0.0
 
 antiAb
Compartment: cell
Initial amount: 0.0
 
 Abeta_antiAb
Compartment: cell
Initial amount: 0.0
 
 AbetaDimer_antiAb
Compartment: cell
Initial amount: 0.0
 
   degAbetaGlia
Compartment: cell
Initial amount: 0.0
 
   disaggPlaque1
Compartment: cell
Initial amount: 0.0
 
   disaggPlaque2
Compartment: cell
Initial amount: 0.0
 
 Source
Compartment: cell
Initial amount: 1.0
Constant
 
 Sink
Compartment: cell
Initial amount: 1.0
Constant
 
Global Parameters (73)
 
   ksynp53mRNA
Value: 0.0010
Constant
 
   kdegp53mRNA
Value: 1.0E-4
Constant
 
   ksynMdm2mRNA
Value: 5.0E-4
Constant
 
   kdegMdm2mRNA
Value: 5.0E-4
Constant
 
   ksynMdm2mRNAGSK3bp53
Value: 7.0E-4
Constant
 
   ksynp53
Value: 0.0070
Constant
 
   kdegp53
Value: 0.0050
Constant
 
   kbinMdm2p53
Value: 0.001155
Constant
 
   krelMdm2p53
Value: 1.155E-5
Constant
 
   kbinGSK3bp53
Value: 2.0E-6
Constant
 
   krelGSK3bp53
Value: 0.0020
Constant
 
   ksynMdm2
Value: 4.95E-4
Constant
 
   kdegMdm2
Value: 0.01
Constant
 
   kbinE1Ub
Value: 2.0E-4
Constant
 
   kbinE2Ub
Value: 0.0010
Constant
 
   kp53Ub
Value: 5.0E-5
Constant
 
   kp53PolyUb
Value: 0.01
Constant
 
   kbinProt
Value: 2.0E-6
Constant
 
   kactDUBp53
Value: 1.0E-7
Constant
 
   kactDUBProtp53
Value: 1.0E-4
Constant
 
   kactDUBMdm2
Value: 1.0E-7
Constant
 
   kMdm2Ub
Value: 4.56E-6
Constant
 
   kMdm2PUb
Value: 6.84E-6
Constant
 
   kMdm2PolyUb
Value: 0.00456
Constant
 
   kdam
Value: 0.08
Constant
 
   krepair
Value: 2.0E-5
Constant
 
   kactATM
Value: 1.0E-4
Constant
 
   kinactATM
Value: 5.0E-4
Constant
 
   kphosp53
Value: 2.0E-4
Constant
 
   kdephosp53
Value: 0.5
Constant
 
   kphosMdm2
Value: 2.0
Constant
 
   kdephosMdm2
Value: 0.5
Constant
 
   kphosMdm2GSK3b
Value: 0.0050
Constant
 
   kphosMdm2GSK3bp53
Value: 0.5
Constant
 
   kphospTauGSK3bp53
Value: 0.1
Constant
 
   kphospTauGSK3b
Value: 2.0E-4
Constant
 
   kdephospTau
Value: 0.01
Constant
 
   kbinMTTau
Value: 0.1
Constant
 
   krelMTTau
Value: 1.0E-4
Constant
 
   ksynTau
Value: 8.0E-5
Constant
 
   kbinTauProt
Value: 1.925E-7
Constant
 
   kdegTau20SProt
Value: 0.01
Constant
 
   kaggTau
Value: 1.0E-8
Constant
 
   kaggTauP1
Value: 1.0E-8
Constant
 
   kaggTauP2
Value: 1.0E-7
Constant
 
   ktangfor
Value: 0.0010
Constant
 
   kinhibprot
Value: 1.0E-7
Constant
 
   ksynp53mRNAAbeta
Value: 1.0E-5
Constant
 
   kdamROS
Value: 1.0E-5
Constant
 
   kgenROSAbeta
Value: 2.0E-5
Constant
 
   kgenROSPlaque
Value: 1.0E-5
Constant
 
   kgenROSGlia
Value: 1.0E-5
Constant
 
   kproteff
Value: 1.0
 
   kremROS
Value: 7.0E-5
Constant
 
   kprodAbeta
Value: 1.86E-5
Constant
 
   kprodAbeta2
Value: 1.86E-5
Constant
 
   kdegAbeta
Value: 1.5E-5
Constant
 
   kaggAbeta
Value: 3.0E-6
Constant
 
   kdisaggAbeta
Value: 1.0E-6
Constant
 
   kdisaggAbeta1
Value: 2.0E-4
Constant
 
   kdisaggAbeta2
Value: 1.0E-6
Constant
 
   kdegAbetaGlia
Value: 0.0050
Constant
 
   kpf
Value: 0.2
Constant
 
   kpg
Value: 0.15
Constant
 
   kpghalf
Value: 10.0
Constant
 
   kactglia1
Value: 6.0E-7
Constant
 
   kactglia2
Value: 6.0E-7
Constant
 
   kinactglia1
Value: 5.0E-6
Constant
 
   kinactglia2
Value: 5.0E-6
Constant
 
   kbinAbetaGlia
Value: 1.0E-5
Constant
 
   krelAbetaGlia
Value: 5.0E-5
Constant
 
   kdegAntiAb
Value: 2.75E-6
Constant
 
   kbinAbantiAb
Value: 1.0E-6
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000488

Curator's comment: (updated: 26 Sep 2013 18:06:33 BST)

Figure 2B (immunisation administered on day 4) of the reference publication has been reproduced here. The model time is in seconds. So, to obtain the result for 12 days, the simulation should be run for 1036800 sec (=12 days). The model was simulated using Copasi v4.10 (Build 55). The plot was generated using Gnuplot.

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