Overview Topics

Monthly Updates

New: April 27, 2001

We have incorporated a new algorithm to determine neuron health. This is still work in progress. (Depending on what web browser you are using, you may need to clear your cache to get the new simulations to load.)

Summary of Updates: Oct 15, 2000

Changes to User Interface

We have eliminated the individual buttons for each cytokine or chemical, and instead implemented a scroll-bar for selecting the display type. This will allow a much larger number of options to be incorporated into the display types.

Astrocytes activation states

The state of an astrocyte (see summary) is now shown explicitly in the display by the color of the cell. Cells become progressively darker as they change from inactive to receptive, to motile. In the most active state, the astrocytes secrete substances that block diffusion and transport of chemicals.

Display astrocytic blocking effects

A new option for the background display is the level of astrocytic effects including the local depression of diffusion and transport of chemicals and cytokines.

Adjusted astrocyte rules.

The motion and behaviour of the astrocytes were adjusted to be more realistic. Here are the updated rules.

Implemented genetic typing

We are implementing the ability to select genetic type. We are currently testing this feature using APOE and its effect on amyloid fiber deposition. Using the work of Yamauchi et al 1999 we have incorporated the distinction between the APOE 2, 3, and 4 types as a scaling of the rate that soluble amyloid is converted to fibrillar amyloid. E4 leads to the largest rate of fiber deposition, and E2, E3, are at the ratios of 7/9, 7/12 of this maximal rate. This set of ratios is based on the ratios of binding affinities of APOE types to A-Beta. To implement this feature, the program reads a parameter file over the internet. This may lead to other network applications.

Introduced two more case studies

We explain the progression and variability of the current simulation.

Summary of Updates: Sept 15, 2000

I. Consultation with Experts

Consultation with P McGeer in August pointed to important areas that merit investigation and inclusion in the simulation. These include: the effects of complement, of apo-lipoprotein E, and of alpha-1-antichymotrypin on the susceptibility to Alzheimer's Disease.

II. Research and Updates to Knowledge Base

Extensive updates to the knowledge base were carried out in the above three new directions, i.e. on complement, apo-lipoprotein E, and alpha-1-antichymotrypin. Numerous papers, both quantitative and descriptive were scanned, and their citations and abstracts incorporated into the current knowledge base. In some cases, citations are now linked directly to the online journal articles. (Some restrictions apply to remote use, or to users without subscriptions to these e-journals.)

III. Summaries of the Literature

A comprehensive set of summaries was prepared for the above three topics. This will gradually be enlarged to include other pertinent literature that has already been used in implementing the past aspects of the simulation. As further detailed quantitative information is obtained, the simulation will be enhanced to include these intermediates.

IV. Progress on Parameters of Neurotoxicity

We have initiated preliminary phases of identifying the possible effects of cytokines on neurotoxicity by direct experimental procedures. Discussions are under way with Jill McEachern (graduate student) and Prof Chris Shaw (UBC and Vancouver General Hospital) on in vitro and in vivo toxicity assays. Currently, Jill is reviewing the scientific literature to summarize what is known, what were the experimental conditions, and how these new experiments should be carried out.

V. Astrocyte Movement and Effect

A thorough revision was carried out for the role of astrocytes, their motion ("gathering at plaque sites"), and their effects. A full description of the current rules is provided. The speed of motion of astrocytes was obtained from a newly-found paper in the literature.

VI. Technical

Currently under consideration are ways to improve the speed of the simulation and streamline the computations.

Summary of Updates: Aug 15, 2000

Two new simulation features have been added to enhance the capabilities of the computation and visualization.

I. Batch Simulations

The user now has an option to run several simulations in parallel, while varying any one parameter. (Select Batch Runs.) The results are compared and plotted at the end of the runs. Plots of neuron health, and of the final displays (both the amyloid level and the state of neuron health in the region) are the final outputs.

II. Zoom Feature

The normal (single run) simulation window has a new zoom feature which allows the user to get a magnified view of any selected area in the simulation window.

III. Bibliography

The scientific literature base has been expanded. Several new topics are being studied for the next round of expansion. These include APO-E, alpha 1 antichymotripsin, and complement. Information about the antagonistic and synergistic effects of these intermediates is being assembled.

Currently in progress

A more accurate representation of the participation of astrocytes is under progress. Evidence that these cells gather at plaques, and that their secretions influence the development of the plaques indicates that more careful details are needed here.

Future Plans

Currently being considered is the ability for the user to add new molecular intermediates to the simulation. The program would prompt the user for the name, properties, and parameters associated with the given chemical, the cells that secrete it, and approximate uptake rates. This will allow customization of the software for individual explorations.

Summary of Updates: July 1, 2000

I. Documentation

The first phase in extensive documentation of the source code was undertaken this month. This was the largest single area of progress. Further documentation is planned.

II. Refinements of the Simulation

The appearance of the simulation was refined in the following ways:

The speed and efficiency of the simulation is undergoing evolution:

III. Validation experiments

A series of tests was carried out with the new settings and parameter values and is described under the heading Behaviour and Reproducibility.

IV. New functionalities under design

Summary of Updates: June 1, 2000

I. Progress on Parameter Estimation

An extensive update of numerous parameters was carried out this month. We identified and summarized literature about the cell-surface receptors for the cytokines IL-1B, IL-6, and TNF, and found cited values for the rates of binding and unbinding of ligands to these receptors. A table listing these results is available. We used values for the number of receptors per cell and the number of cells per unit volume to convert these values to realistic rates of uptake of cytokines. A web page listing the literature values was created, and linked to extensive documentation about the scientific literature on this subject.

We also refined our estimates of amyloid fibrillogenesis by using a number of citations about the effects of ionic composition similar to that of the brain on the aggregation of soluble amyloid. Updates for the supporting web page are under progress.

II. Refinements of the Simulation

The simulation underwent major revision to correct for the way that cytokines and amyloid are removed by cells. This resulted in fewer parameters, more well-defined parameters, and changes in the assumptions (previously ad hoc) to reflect mass action kinetics of receptors and ligands. In a future revision, we will be able to incorporate receptor down-regulation and internalization, though this is not yet in place.

A significant revision was carried out to the visual aspect of the simulation: images of actual neuronal tissue can now be incorporated as a possible background, and as the glial cells are represented by more realistic cell icons, in place of ovals in a new version of the program. This change was in response to a suggestion by Prof Sue Griffin to improve the visual attributes. It required some new programming tricks (double buffering) to eliminate problems with flashing and choppy display.
In future refinements, we may show the changes in morphology that accompany activation of cells, or a variety of neuronal tissue background.

We revised the way that cells are represented in the region. The size of our current volume is 16 x 105 cubic microns. Thus, a lower estimate for number of microglia in this region would be 500 and an upper estimate would be 1800. As it is unreasonable to display and recompute positions of so many individual cells, we now use each moving "unit" to represent the effect of multiple cells while preserving the proportions 40 microglia : 40 neurons : 100 astrocytes. Two of the parameters that we have added, "microglia concentration" and "astrocyte concentration" are the factors used to designate how many cells are represented by one moving "unit". We are thus able to more accurately depict the effect of the glial cell density in the region.

III. Content and Format Changes There were numerous cosmetic changes as requested during the month, including links on most pages to navigate back to overview topics.

IV. Validation Experiments

A number of experiments have been carried out with the current simulation, as described in detail on summary web pages. These are among the earliest scientific results of the simulation, and use some of the features that we have incorporated. One example is the ability to use the mouse to "click away" a stimulus source during the course of a run. We used this feature to explore the consequences of removing the initial stimulus at various times. These experiments show the effect of removal of the early stimulus, and the resulting delay in development of partial neuronal degeneration. More validation experiments are planned.

V. Other Changes

Further updates of the literature base and extensive links from papers to tables, to abstracts were incorporated.

VI. Future Plans

Summary of Updates: May 1, 2000

I. Progress on Parameter Estimation

Discussions were held with Prof S Griffin to narrow down parameter values for amyloid critical concentration at which fibers form, and for the neurotoxicity of cytokines. Prof Griffin was unable to help us identify these values. We are continuing to search the literature.

II. Refinements of the Simulation

Astrocyte chemotaxis and motion was removed following advice by neuroscientists. The astrocytes are now stationary.

III. Content and Format Changes

An extensive list of references and abstracts were put onto the web, and arranged by topic. This was one of the major labour intensive developments of the past month. Important aspects of these citations were highlighted. Where possible, links from parameters to these references were indicated. This base of references will be expanded and further links will be made in due time.

IV. Other Changes

The simulation now includes a new feature: the ability to remove a source of stress-inducing signal at any point during the run. This feature will enable us to determine whether removal of this stimulus early enough could prevent some of the effects leading up to neuronal death.

V. Future Plans

(a) We plan to introduce the possibility of partial neuronal recovery and examine the effect of various interventions on that recovery. (b) Following advice from Prof Griffin, we plan to make the simulation more visually appealing by using realistic pictures of cells (in place of ovals), and showing changes in their morphology as they are activated. (c) We are making the growth of plaques more realistic, and incorporating a direct link between amyloid and neuronal health. (d) We are considering navigational aids and clearer organization of the web pages. (e) We plan to gradually update and improve the parameter descriptions, the simulation description, and other aspects of the web pages.

Summary of Updates: April 1, 2000

New Look for Demo and Simulation

The simulation has been given a new look. All front-end buttons are now placed to the right of the active simulation window to avoid the need for scrolling up and down while making selections. This should reduce the distractions due to browser display difficulties.

TNF Added

The cytokine, TNF-alpha, has been added to the simulation. Users can now see the effects of TNF, which is currently secreted by astrocytes and taken up by neurons. The current implementation allows the user to specify whether TNF is helpful or harmful to neurons (the default is for TNF to protect neuron health). The parameter TNF effect determines whether TNF is neurotoxic (negative values) or neuroprotective (positive values). The effect of TNF interacts with the effect of IL-6, as described in the simulation details.

Manipulate Graph Data

A new button (labeled "Show data") has been added to the graph window for overall neuron health. Selecting this option enables the user to get the coordinates that make up points on the graph. The data can be copied to a file which can then be manipulated by any software package such as Excel to summarize the results of multiple runs.

Web Pages Updated

All the web pages have been expanded and updated to reflect these changes (e.g. the tutorial).

Summary of Updates: March 1, 2000

The Demo and Simulation Pages

The extensive text on the bottom of these pages has been replaced by hypertext links to separate pages with details about the simulation and demo and information about how to run the simulation and the demo.

Tutorial and Instructions

Detailed instructions for running the simulation and a full description of the available options is now in place as a tutorial.

Parameter Values

Pages of Parameter values have been separated and tagged so that the links on the demo page lead directly to the tables and references supporting the values. New tables are in place, and others are being prepared. (A table for chemotaxis coefficients of cells has been added.)

Status of Parameter Values

A summary page has been prepared listing all the current parameter values used in the simulation and indicating the status of each of the parameters, i.e. whether based on biological values, calculated, or still not calibrated.

New Information about Neurotoxicity

An extensively referenced web-page with details about neurotoxicity has been added. This page represents new information found in the literature that will gradually be incorporated into the simulation.

Summary of Simulation Updates: Feb. 1, 2000

Units on Display

Lengths are measured in microns, time is measured in minutes, and concentrations are measured in nM.


Time steps

Changes to Amyloid-Beta

Soluble form

Fiber Formation

New information on fiber growth has lead us to change the fiber formulation. It has been shown that fibers need a critical concentration of soluble Amyloid-beta to grow. Thus, the parameter critical sol-AB for fibers has been introduced to the simulation. Studies also reveal that fibers do not shrink, so fiber degradation has been removed from the simulation. Finally, the current formulation only allows for fibers to grow where they exist; they cannot grow spatially.

Changes to Microglia


The disruption of movement due to fibers has been reformulated. Studies show that microglia get stuck with an increase of the fiber concentration at a probability that fits a Michaelis-Menten relation. Thus, the parameter half hazardous fiber level is introduced to indicate at what fiber concentration the microglia have a 50% chance of getting stuck. However, an increase in the concentration of soluble amyloid-beta tends to lower the probability of getting stuck. We model this with an exponential decay, where the new parameter half soluble slipping level indicates the concentration of soluble amyloid-beta present for a stuck cell to have a 50% chance of moving.

Amyloid-Beta Absorption

The absorption of amyloid-beta by microglia also had to be reformulated to fit the data. The rate of absorption follows a Michaelis-Menten relation based on the concentration of soluble amyloid-beta present. Thus, we introduce two new parameters for these kinetics. Half the maximum sol-AB absorption rate occurs when the amyloid-beta concentration is at the half max amyloid binding conc.

IL-1B secretion

Changes to Astrocytes

Changes to IL-1B and IL-6

Changes to Neurons

No significant data as of yet. Simply scaled current parameter values to be close to others in the simulation.