May, 2000

Goal: To determine the effect that removal of the initial stress-inducing stimulus has on the overall health of neurons, given that IL-1 causes a decline in neuronal health.

Hypothesis: If the stimulus that initiates the cascade of effects is removed early enough, it should be possible to halt neuron death, or to prevent a large proportion of the neurons from dying. However, neuronal death may continue beyond the timing of the source removal.

Method: As in Case Study 1a, this study examined a simplified setting in which only microglia and neurons interact. Astrocytes were removed (by setting "initial astrocyte count" parameter to zero). Contrary to the previous case study, it was assumed that IL-1B has a direct effect on neuronal health. (The parameter

"IL-1B effects on health" was set to -1.0, to signify injury to neurons when absorbed.) The simulation was run as before, with the source removed at time t=25. (I.e., at time 25, the simulation was stopped, the change amyloid parameter box was selected, the "remove source" button was selected , and the mouse was used to click away the single source of stimulus at the center of the domain.).The accumulation of IL-1b, and the resulting death of neurons was followed.

Parameters used:

Observations and conclusions: With the current set of parameters and assumptions, the effect of IL-1B on neuron degeneration is rapid and irreversible. As soon as IL-1B is produced and absorbed in sufficient quantity, neurons start to die locally.

Although the removal of the initial stimulus by time t=25 prevents the production of new sources of amyloid (see Case Study 1a), it does not necessarily confer resistance to direct IL-1B induced stress and death.

We also observe that at the time that the intervention occurs, i.e. at time t=25, few if any neurons have been damaged, and IL-1B is only beginning to accumulate. There is an inherent delay in the cascade: it takes time for microglia to react to the initial stimulus, to absorb this stimulus and to gradually secrete IL-1B in response. There is a further delay in the absorption of sufficient quantities of IL-1B to stress or kill a given block of neuronal tissue.

For the given set of parameters and assumptions, some decline in overall neuronal health and in the number of neurons that die occurs, even when the initial stimulus is short-lived (till t=25 only). However, from the graph below we observe that the decline in health stops eventually: just past time t=100, the neuronal health stabilizes at approximately 55% as shown on the graph below. Not all the neurons in the region will die.

These results would vary if parameters for neuronal stressing, rates of absorption of IL-1b, or effect of IL-1B on neuronal health were to be altered.

This simulation highlights the fact that interventions upstream of the actual neuronal injury or death may not have immediate effects on the degeneration, though ultimately they may reduce or alleviate part of the problem. This simulation did not include effects that promote neuron recovery, and so this is another interesting direction to pursue in future experiments.

Fig 1: Altough the initial stimulus was removed at t=25, neurons started to degenerate up to time 106. Thereafter, their health no longer declined.