Please visit the new BioModels platform to access the latest content. This website is no longer updated and will be retired on 31 May 2019.
BioModels Database logo

BioModels Database


Proctor et al., (2013). Investigating interventions in Alzheimer's disease with computer simulation models.

August 2014, model of the month by Audald Lloret-Villas
Original model: BIOMD0000000488


Immunisation is a novel and promising development in the reduction of Amyloid beta (Aβ) and Tau protein aggregation, which are the main features in neurodegenerative diseases such Alzheimer’s Disease (AD) [1]. This phenomenon seems to solubilize Aβ for antibody action and to phagocyte Aβ due to microglia activity [2].


Proctor et al., (2013) [3, BIOMD0000000488], by integrating and extending their previous models on Aβ and tau protein aggregation process [4,BIOMD0000000286] and the role of Aβ dimer formation in aggregating process [5, BIOMD0000000462], developed a model including the main processes involved in the passive and active immunisation against Aβ. The model describes the effect of immunisation against Aβ on soluble Aβ, plaques, phosphorylated tau and tangles. The general scheme of the model is represented in Figure 1.

Figure 1

Figure 1General overview of reactions leading to aggregation of Aβ and tau, and the effect of immunisation against Aβ. Figure taken from [3].

Proctor et al., (2010) [4, BIOMD0000000286] describes the interaction between GSK3β, p53, Aβ and tau in AD. This model referred as "GSK3/p53 hypothesis", is illustrated in Figure 2. Proctor et al., (2012) [5, BIOMD0000000462] describes and examines Aβ turnover rates and levels of Aβ dimer in the initiation of the aggregation process. A short review of these two models as previous "Model of the Month" articles in BioModels Database can be seen at MoM_July2013 and MoM_May2014.

Figure 2

Figure 2Network diagram of the GSK3/p53 model [3]. Dotted line denote metabolite sources, dashed line denote metabolite waste, red arrow denote modifiers and black arrow denote reactions. Top left: p53 pathway. Top right: Tau tangles formation. Bottom: Aβ plaques formation.

The extended model [3] includes the processes involved in passive Aβ immunisation using antibodies, as the reduction of tau phosphorylation is hypothesised to be the consequence of this immunisation. There are three possible effects of antibodies [6]:

  • Enhanced degradation of soluble Aβ.
  • Enhanced disaggregation of Aβ plaques.
  • Activation of microglia to engulf and phagocytes plaques.

Simulations are plotted using low degradation rate of Aβ and varying the parameters in turn from half to double its initial value in order to check Aβ and tau sensibility toward them.


Model predictions have shown that there is a same amount of Aβ production in all the subjects but the rate of degradation is lower in AD subjects than the control subjects. In fact,immunisation reduces the level of Aβ plaques even though the soluble Aβ decreases only to a small amount. Additionally, the model predictions suggested that there is slower kinetics in tau phosphorylation and aggregation after repeated interventions due to the decreased activation of p53 and GSK3β via ROS. However, a minimum reduction of GSK3β that is detected after immunisation, is not sufficient to significantly reduce the levels of phospho-tau. Model predictions are represented in Figure 3. On the other hand, it is demonstrated that there are no parameters that can affect only Aβ without affecting tau aggregation.

Figure 3

Figure 3Model predictions for Aβ and Tau levels. Passive immunisation administered on: A) day 0; B) day 4; C) day 8; D) day 0 and 7; E) active immunisation; F) no immunisation. Colour key: orange soluble Aβ; blue Aβ plaques; green Tau; black Tau tangles; red activated glia . Figure taken from [3].


The effects of immunisation against Aβ in Aβ and Tau aggregation are explored using a mathematical model. As the associated biologically relevant pathways become available, the model can become increasingly accurate and can possibly be useful in clinical testing of neurodegenerative diseases, especially Alzheimer’s Disease.


  1. Crews et al. Molecular mechanisms of neurodegeneration in Alzheimer's disease. Hum Mol Genet. (2010); 19(R1):R12-20.
  2. Boche et al. Neuropathology after active Abeta42 immunotherapy: implications for Alzheimer's disease pathogenesis. Acta Neuropathol. (2010); 120(3):369-84.
  3. Proctor et al. Investigating interventions in Alzheimer's disease with computer simulation models. Plos One. (2013); 8(9);e73631. doi; 10.1371
  4. Proctor et al. GSK3 and p53 - is there a link in Alzheimer's disease? Mol Neurodegener. (2010); 5:7. doi:10.1186/1750-1326-5-7.
  5. Proctor et al. Aggregation, impaired degradation and immunization targeting of amyloid-beta dimers in Alzheimer's disease: a stochastic modelling approach. Mol Neurodegener. (2012); 7:32. doi:10.1186/1750-1326-7-32.
  6. Zotova et al. Microglial alterations in human Alzheimer's disease following Aβ42 immunization. Neuropathol Appl Neurobiol (2011); 37(5):513-24