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ATMInactivation

ATMA > ATMI

ATMactivation

damDNA + ATMI > damDNA + ATMA

AbetaAggregation1

{2.0}Abeta > AbetaDimer

AbetaBindingToGlia

AbetaPlaque + GliaA > AbetaPlaque_GliaA

AbetaDegradation

Abeta > Sink

AbetaDimer_antiAbBinding

AbetaDimer + antiAb > AbetaDimer_antiAb

AbetaDimer_antiAbDegredation

AbetaDimer_antiAb > antiAb

AbetaDisaggregation1

AbetaDimer > {2.0}Abeta

AbetaDisaggregation3

AbetaPlaque > AbetaDimer + disaggPlaque1

AbetaDisaggregation4

AbetaPlaque + antiAb > AbetaDimer + antiAb + disaggPlaque2

AbetaPlaqueClearanceByGlia

AbetaPlaque_GliaA > GliaA + degAbetaGlia

AbetaPlaqueFormation1

{2.0}AbetaDimer > AbetaPlaque

AbetaPlaqueGrowth

AbetaDimer + AbetaPlaque > {2.0}AbetaPlaque

AbetaROSproduction1

Abeta > Abeta + ROS

AbetaReleaseFromGlia

AbetaPlaque_GliaA > AbetaPlaque + GliaA

Abeta_antiAbBinding

Abeta + antiAb > Abeta_antiAb

Abeta_antiAbDegredation

Abeta_antiAb > antiAb

Abetaproduction1

Source > Abeta

Abetaproduction2

GSK3b_p53 > Abeta + GSK3b_p53

Abetaproduction3

GSK3b_p53_P > Abeta + GSK3b_p53_P

AggAbetaROSproduction2

AggAbeta_Proteasome > AggAbeta_Proteasome + ROS

DNAdamage

IR > IR + damDNA

DNArepair

damDNA > Sink

Degradationp53_Ub4

p53_Ub4_Proteasome + ATP > {4.0}Ub + Proteasome + ADP

E1UbBinding

E1 + Ub + ATP > E1_Ub + AMP

E2UbBinding

E2 + E1_Ub > E2_Ub + E1

GSK3_p53PRelease

GSK3b_p53_P > GSK3b + p53_P

GSK3p53Binding

GSK3b + p53 > GSK3b_p53

GSK3p53PBinding

GSK3b + p53_P > GSK3b_p53_P

GSK3p53Release

GSK3b_p53 > GSK3b + p53

GliaActivationStep1

GliaI + AbetaPlaque > GliaM1 + AbetaPlaque

GliaActivationStep2

GliaM1 + AbetaPlaque > GliaM2 + AbetaPlaque

GliaActivationStep3

GliaM2 + antiAb > GliaA + antiAb

GliaInactivationStep1

GliaA > GliaM2

GliaInactivationStep2

GliaM2 > GliaM1

GliaInactivationStep3

GliaM1 > GliaI

Mdm2Degradation

Mdm2_Ub4_Proteasome > Proteasome + {4.0}Ub

Mdm2Deubiquitination1

Mdm2_Ub + Mdm2DUB > Mdm2 + Mdm2DUB + Ub

Mdm2Deubiquitination2

Mdm2_Ub2 + Mdm2DUB > Mdm2_Ub + Mdm2DUB + Ub

Mdm2Deubiquitination3

Mdm2_Ub3 + Mdm2DUB > Mdm2_Ub2 + Mdm2DUB + Ub

Mdm2Deubiquitination4

Mdm2_Ub4 + Mdm2DUB > Mdm2_Ub3 + Mdm2DUB + Ub

Mdm2GSK3phosphorylation1

Mdm2_p53_Ub4 + GSK3b > Mdm2_P1_p53_Ub4 + GSK3b

Mdm2GSK3phosphorylation2

Mdm2_p53_Ub4 + GSK3b_p53 > Mdm2_P1_p53_Ub4 + GSK3b_p53

Mdm2GSK3phosphorylation3

Mdm2_p53_Ub4 + GSK3b_p53_P > Mdm2_P1_p53_Ub4 + GSK3b_p53_P

Mdm2PDegradation

Mdm2_P_Ub4_Proteasome > Proteasome + {4.0}Ub

Mdm2PDeubiquitination1

Mdm2_P_Ub + Mdm2DUB > Mdm2_P + Mdm2DUB + Ub

Mdm2PDeubiquitination2

Mdm2_P_Ub2 + Mdm2DUB > Mdm2_P_Ub + Mdm2DUB + Ub

Mdm2PDeubiquitination3

Mdm2_P_Ub3 + Mdm2DUB > Mdm2_P_Ub2 + Mdm2DUB + Ub

Mdm2PDeubiquitination4

Mdm2_P_Ub4 + Mdm2DUB > Mdm2_P_Ub3 + Mdm2DUB + Ub

Mdm2PProteasomeBinding1

Mdm2_P_Ub4 + Proteasome > Mdm2_P_Ub4_Proteasome

Mdm2PUbiquitination

Mdm2_P + E2_Ub > Mdm2_P_Ub + E2

Mdm2PpolyUbiquitination1

Mdm2_P_Ub + E2_Ub > Mdm2_P_Ub2 + E2

Mdm2PpolyUbiquitination2

Mdm2_P_Ub2 + E2_Ub > Mdm2_P_Ub3 + E2

Mdm2PpolyUbiquitination3

Mdm2_P_Ub3 + E2_Ub > Mdm2_P_Ub4 + E2

Mdm2ProteasomeBinding1

Mdm2_Ub4 + Proteasome > Mdm2_Ub4_Proteasome

Mdm2Synthesis

Mdm2_mRNA > Mdm2_mRNA + Mdm2

Mdm2Ubiquitination

Mdm2 + E2_Ub > Mdm2_Ub + E2

Mdm2dephosphorylation

Mdm2_P > Mdm2

Mdm2mRNADegradation

Mdm2_mRNA > Sink

Mdm2mRNASynthesis1

p53 > p53 + Mdm2_mRNA

Mdm2mRNASynthesis2

p53_P > p53_P + Mdm2_mRNA

Mdm2mRNASynthesis3

GSK3b_p53 > GSK3b_p53 + Mdm2_mRNA

Mdm2mRNASynthesis4

GSK3b_p53_P > GSK3b_p53_P + Mdm2_mRNA

Mdm2phosphorylation

Mdm2 + ATMA > Mdm2_P + ATMA

Mdm2polyUbiquitination1

Mdm2_Ub + E2_Ub > Mdm2_Ub2 + E2

Mdm2polyUbiquitination2

Mdm2_Ub2 + E2_Ub > Mdm2_Ub3 + E2

Mdm2polyUbiquitination3

Mdm2_Ub3 + E2_Ub > Mdm2_Ub4 + E2

P53Mdm2Binding

p53 + Mdm2 > Mdm2_p53

P53Mdm2Release

Mdm2_p53 > p53 + Mdm2

PlaqueROSproduction

AbetaPlaque > AbetaPlaque + ROS

ProteasomeInhibitionAbeta

AbetaDimer + Proteasome > AggAbeta_Proteasome

ProteasomeInhibitionAggTau

AggTau + Proteasome > AggTau_Proteasome

ROSDNAdamage

ROS > ROS + damDNA

ROSgenerationByGlia

AbetaPlaque_GliaA > AbetaPlaque_GliaA + ROS

ROSremoval

ROS > Sink

TangleFormation1

{2.0}AggTau > {2.0}NFT

TangleFormation2

AggTau + NFT > {2.0}NFT

Tau20SProteasomeDegradation

Proteasome_Tau > Proteasome

TauAggregation1

{2.0}Tau > {2.0}AggTau

TauAggregation2

Tau + AggTau > {2.0}AggTau

TauMTbinding

Tau > MT_Tau

TauMTrelease

MT_Tau > Tau

TauP1Aggregation1

{2.0}Tau_P1 > {2.0}AggTau

TauP1Aggregation2

Tau_P1 + AggTau > {2.0}AggTau

TauP2Aggregation1

{2.0}Tau_P2 > {2.0}AggTau

TauP2Aggregation2

Tau_P2 + AggTau > {2.0}AggTau

TauProteasomeBinding

Tau + Proteasome > Proteasome_Tau

TauSynthesis

Source > Tau

Taudephosphorylation1

Tau_P2 + PP1 > Tau_P1 + PP1

Taudephosphorylation2

Tau_P1 + PP1 > Tau + PP1

Tauphosphorylation1

GSK3b_p53 + Tau > GSK3b_p53 + Tau_P1

Tauphosphorylation2

GSK3b_p53 + Tau_P1 > GSK3b_p53 + Tau_P2

Tauphosphorylation3

GSK3b_p53_P + Tau > GSK3b_p53_P + Tau_P1

Tauphosphorylation4

GSK3b_p53_P + Tau_P1 > GSK3b_p53_P + Tau_P2

Tauphosphorylation5

GSK3b + Tau > GSK3b + Tau_P1

Tauphosphorylation6

GSK3b + Tau_P1 > GSK3b + Tau_P2

antiAbRemoval

antiAb > Sink

p53Deubiquitination1

Mdm2_p53_Ub + p53DUB > Mdm2_p53 + p53DUB + Ub

p53Deubiquitination2

Mdm2_p53_Ub2 + p53DUB > Mdm2_p53_Ub + p53DUB + Ub

p53Deubiquitination3

Mdm2_p53_Ub3 + p53DUB > Mdm2_p53_Ub2 + p53DUB + Ub

p53Deubiqutination4

Mdm2_p53_Ub4 + p53DUB > Mdm2_p53_Ub3 + p53DUB + Ub

p53Monoubiquitination

E2_Ub + Mdm2_p53 > Mdm2_p53_Ub + E2

p53Polyubiquitination1

Mdm2_p53_Ub + E2_Ub > Mdm2_p53_Ub2 + E2

p53Polyubiquitination2

Mdm2_p53_Ub2 + E2_Ub > Mdm2_p53_Ub3 + E2

p53Polyubiquitination3

Mdm2_p53_Ub3 + E2_Ub > Mdm2_p53_Ub4 + E2

p53ProteasomeBinding1

Mdm2_P1_p53_Ub4 + Proteasome > p53_Ub4_Proteasome + Mdm2

p53Synthesis

p53_mRNA > p53 + p53_mRNA

p53dephosphorylation

p53_P > p53

p53mRNADegradation

p53_mRNA > Sink

p53mRNASynthesis

Source > p53_mRNA

p53phosphorylation

p53 + ATMA > p53_P + ATMA

p53transcriptionViaAbeta

Abeta > p53_mRNA + Abeta

Parameters

Global parameters

Fixed species

Initial values

Functions and Rules

Events

ImmunizeCell

Trigger: geq(time, 345600)

Delay:

Assignments:

  • antiAb = 50

Constraints

Note that constraints are not enforced in simulations. It remains the responsibility of the user to verify that simulation results satisfy these constraints.


Species:

Reactions:

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Investigating interventions in Alzheimer's disease with computer simulation models.

  • Carole J Proctor
  • Delphine Boche
  • Douglas A Gray
  • James A R Nicoll
PLoS ONE 2013; 8 (9):
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.
The SBML for this model was obtained from the BioModels database (BioModels ID: BIOMD0000000488) Biomodels notes: 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. JWS Online curation: This model was curated by reproducing the figures as described in the BioModels Notes. No additional changes were made.