Overview Topics

May, 2000

Case Study 2:

Formation of Diffuse Plaques

Goal: to investigate the dynamics of growth of amyloid deposits around a source of soluble amyloid, given that microglia absorb and remove soluble amyloid.

Hypothesis: The formation of fibrous deposits may depend on the initial distribution of glial cells and nucleation sites. It should also depend on the efficiency of removal of soluble amyloid by the microglia.

Method: The simulation was run with microglia and amyloid (no astrocytes). In this simulation we did not investigate neuron health, and we were not considering the formation of new sources of amyloid. We were interested only in the deposition of amyloid fibers around a source of soluble amyloid, and the effect of microglia amyloid uptake.

The simulation was run twice for each parameter set: In one run, the initial conditions were chosen so that fiber nuclei were seen in proximity of the source. In a second run, the initial conditions were selected to favor microglial abundance close to the source. The parameter sets for which the simulation was run include one in which the microglia were efficient at removing and degrading amyloid (Runs 1 and 2) and one set in which the microglia were less efficient (Runs 3 and 4). A list of the parameter values follows at the end of the description.

Observations: If the fiber nuclei were, by chance, in proximity of the source there was a slight tendency for the diffuse plaque to form closely enveloping the site of soluble amyloid production. (See Runs 2, 4). If the microglia were, by chance, initially closer to the source than the amyloid deposits, the diffuse plaque tended to have a hollow center, since the microglia localized rapidly at the source and removed amyloid before it could cause deposits to grow.

For the parameter set in which the microglia were less efficient at amyloid removal, the level of soluble amyloid, and hence also the deposition of the fibers into diffuse plaques was more rapid and pervasive.

Remarks: Results would be sensitive to the magnitude of the amyloid source, the rate of uptake and disposal of amyloid by microglia, and other parameters relevant to amyloid deposition (e.g. critical concentration of amyloid, nucleation rate, and rate of growth of fibers.) The latter parameters are known to depend on the ionic composition (e.g. on the presence of Cu++, Mg++, and other ions.



Time t=0

Time t=100

Time t=200

Run 1

Run 2

Run 3

Run 4


Parameters for Runs 1, 2 : Runs 3, 4
(Parameters that are different between Runs 1, 2 and Runs 3, 4 are shown in bold.)

Chemical Parameters
diffusivity = 1499.
source concentration = 200.0
initial fiber occupancy = 0.039
critical sol-AB for fibers = 19.2
new fibre nucleation effectiveness1.0
sol to fiber transition rate (times 10^(-6)) = 10.0

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 = 0.392 : 0.1
half max amyloid binding conc = 15.0
chemical breakdown = 0.416 : 0.01

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 = 56.0
maximum IL-1B absorbed = 35.0
IL-1B effects on health = 0.0