Overview Topics

May, 2000

Case Study 1a:

Stimulus Removal: Effect on Amyloid Secretion by Neurons


Goal: To determine the effect of removal of the initial stress-inducing stimulus on the behaviour and eventual outcome: specifically, on the triggering amyloid secretion by neurons.

Hypothesis: If the stimulus that initiates the cascade is removed early enough, downstream effects such as the formation of new sources of amyloid should not occur. One expects that the duration of the stress inducing signal should be affect the buildup of injurious cytokines to thresholds that trigger further effects.

Method: For this experiment, astrocytes were removed (the parameter initial astrocyte count was set to zero). This results in a simulation in which microglia, IL-1Beta, and neurons interact. ( The absence of astrocytes also implies that no IL-6 or TNF are being produced.) In the current run, the effect of IL-1B on neuron health was kept neutral, and only the eventual triggering of amyloid sources was studied.


Run 1: The simulation was run for 21 time points with the initial stimulus present


(1b) At time t=21, the central signal was removed, and the simulation continued. The microglia continue

to secrete some IL-1B for a time, but this cytokine never built up to levels high enough to cause new sources to form.


With time, the chemical concentration in the domain was reduced: neither Il-1B nor amyloid accumulated in the domain, and the neurons never produced new sources.


Run 2: An identical simulation was started, but the initial stimulus (red source in center) was left on until time t=31 and then removed. The microglia had already been activated strongly enough to continue producing IL-1B even though the signal had been removed. At time t=114 new sources of amyloid had been triggered in the neurons due to the IL-1B that they had absorbed.


Parameters used:

Chemical Parameters
diffusivity = 1499.
source concentration = 200.0
initial fiber occupancy = 0.081
critical sol-AB for fibers = 24.4

Microglia Parameters
initial microglia count = 40.0
maximum density = 3.0
motility time delay = 14.0
chemotactic sensitivity = 0.67
half-sticking fiber level = 50.0
half-sticking sAB level = 20000
maximum sAB microglia uptake rate = 0.1
half max amyloid binding conc = 15.0
chemical breakdown = 0.01
fatal dosage = 1.0

Astrocyte Parameters
Initial astrocyte count = 0.0

IL-1B Parameters
IL-1B diffusivity = 899.6
triggering concentration = 0.5
IL-1B secretion rate = 0.36

Neuron Parameters
IL-1B absorption rate = 0.18
source triggering level = 18.0
maximum IL-1B absorbed = 35.0
IL-1B effects on health = 0.0


Other experiments performed: To test sensitivity to parameters, the same simulation was run with several changes: (a) altering the chemotaxis of microglia (rationale: preventing the microglia from arriving quickly at the stimulus site may slow the process). (b) changing the rate of secretion of IL-1B by microglia (rationale: this could reduce the level of IL-1B in the region, and delay the triggering that causes neurons to secrete amyloid.) (c) changing the rate of absorption of IL-1B by neurons (same rationale as in b).

Results: Of the above experiments only (c) was significant in changing the time at which the new sources of amyloid were formed. Otherwise, the new sources generally formed by time t=110 and this time was relatively independent of parameter changes in (a) and (b) .


Observations and conclusions: With current parameter values, and model assumptions, the initial stress-inducing stimulus has a rapid effect on the cascade of events, and in particular, on the formation of new amyloid sources by neurons. If the stimulus is removed early (before time t=25), the triggering of such sources does not occur. Otherwise, removal of the initial signal is unable to stop the irreversible process that is initiated.

The insensitivity of the time at which new sources were initiated suggests that the way in which IL-1B levels affect neuronal triggering is not accurate in the present simulation, and that this should be changed.