Figure 1: Light microscope images of senile plaques and arrangement of glial cells in human AD brain. (a) Staining for Amyloid beta-42, showing the characteristic morphology and distribution of amyloid at plaques. (b) Localization of microglia in the center (brown : CR3-43 stain) and surrounding ring of astrocytes (magenta, star-like shapes, GFAP stain) at a plaque site. (c) Congregation of microglia (dark purple shapes CR3-43 stain) and nuclei of other cells (Neutral red stain) at a plaque. Small tick marks represent 10 microns in each frame. Images kindly supplied by Claudia Schwab and used with permission of the McGeer group, Kinsmen Laboratory, University of British Columbia.
Figure 2: Schematic diagram showing some of the interactions considered in the simulation: Soluble amyloid causes microglial chemotaxis, and activates IL-1B secretion.
Astrocytes activated by IL-1B secrete cytokines TNF and IL-6. Neurons uptake IL-1B and produce new amyloid sources. A variety of assumptions were explored about what causes stress and death of neurons.
Figure 3: TOP ROW: Formation of a plaque and death of neurons in the absence of glial cells, when fibrous amyloid is the only injurious influence. The simulation was run with no astrocytes or microglia, and health of neurons was determined solely by the local fibrous amyloid. Shown above is a time sequence (left to right) of three stages in plaque development, at times t=20, 60, 400 minutes. Density of fibrous deposit is represented by small dots and neuronal health by shading from white (healthy) to black (dead). Note radial symmetry due to simple diffusion (Fibonly). BOTTOM ROW: Effect of microglial removal of amyloid on plaque morphology. Note that microglia (small star-like shapes) are seen approaching the plaque (via chemotaxis to soluble amyloid, not shown). At a later stage, they have congregated at the plaque center, where they adhere to fibers. As a result of removal of soluble and fibrous amyloid, the microglia lead to irregular plaque morphology. (Fibmic). Size scale: In this and all other figures, the distance between the small single dots (representing low fiber deposits) is 10 microns
Figure 4: The secretion of the cytokine IL-1B (not here shown) by microglia is assumed to promote processing of APP and lead to new sources of beta amyloid in the tissue. This results in formation of new plaque sites at the periphery of the initial plaque, or possibly much heavier deposition of fiber in the central plaque. The stochastic nature of the simulation means that the number of new sources, and their locations are somewhat random, leading to quite variable results. The diameter of the plaque in (c) is about 120 microns. All runs shown at t=800. (fibmicIL1)
Figure 5: Average neuron health over time, showing variability in the runs of Figure 4.
Figure 6: Relative positions of microglia (star shaped cells in center) and astrocytes (small fuzzy disks) next to a putative fiber deposit. Microglia have been attracted to an amyloid source at the center, and astrocytes have gathered at the edge of the fiber deposit. The effect of astrocytic blocking is shown by shaded areas. These are regions of reduced diffusion of chemicals.
Figure 7: A variety of shapes and sizes of plaques obtained with astrocytes included in the interactions. Length of bar: 100 microns.
Figure 8: Variability in neuronal health dynamics in runs with parameters as in Fig 7.
Figure 9: Size distribution of the plaques obtained in runs with parameters as in Figures 6 and 7 (dark bars) shown next to the size distribution obtained from an AD brain by Hyman et al (1995) (light bars). The horizontal axis represents plaque areas in multiples of 100 microns2. The last category represents all larger plaques that were obtained.
Figure 10: The evolution of a growing plaque under the effect of astrocyte blocking is shown here (for another parameter set) at times t=50, 300, 750, and 1200. Astrocytes significantly affect the morphology of the plaque, leading to an irregular central dead region surrounded by smaller “sprouts” in places where the toxic influence of amyloid has leaked through breaks in the sealed-off region.
Figure 11(a-e): A typical time sequence (t= 40, 80, 200, 230, 270 from left to right, top to bottom) showing changes in neuron health due to a diffusible toxic product of activated astrocytes. The amyloid source causing microglia to secrete IL-1B was gone by t=130 (due to neuronal death). This eventually stopped astrocytic secretion, but stress and further death continued until about t=210, due to time for gradual removal and decay of the inflammatory substances. Once the chemical levels had fallen, a fairly rapid recovery occurred in those regions that had not died, leaving a small core of dead neurons in the center. Here amyloid fiber has no effect on neuronal health directly. (f) A plot of the neuronal health for this time sequence. (IL6toxfib)
Figure A1: Neuronal health is represented by an aggregate value which ranges from h=1 (or 100%) for full health to h=0 for dead neurons. Shown here is the rate of change of neuronal health (dh/dt) as a function of current health (h) for three values of the injurious influence, I. The directions of the arrows indicate increasing health (to the right) or decreasing health (to the left) (a) No injurious influence (I=0): health increases up to full recovery at h=1 regardless of the initial state. (b) 0<I<r/4 Intermediate level of toxicity. Here neurons will become partially stressed (i.e. approach the steady state marked by heavy dot) unless they are already in very low health. In the latter case, they would die. (c) I>r/4 :This is a fatal level of toxicity and all states lose health and die unless the toxic influence is removed.