Overview Topics |
The potential contribution of circulating monocytes/macrophages to the inflammatory process of Alzheimer's disease (AD) is studied in a physiological model proposed by Fiala et al. [1].
Under normal circumstances, the blood-brain barrier (BBB) filters out the circulating monocytes from the brain tissue. However, chemotactic stimulus of inflammatory regions of the brain may attract such monocytes which then permeate the BBB. A large number of Aß deposits are present in the AD brain together with the presence of multiple inflammatory molecules. These are thought to induce the monocytes transmigration of the BBB, and movement into the vicinity of Aß deposits.
Differentiation of monocytes into macrophages:
Aß induces secretion of cytokines by cultured monocytes:
A-b(mg/ml) | TNF-a(pg/ml) | IL-6(pg/ml) | IL-12(pg/ml) | IL-1b(pg/ml) |
0.25 | 500 | 20 | 1 | |
2.5 | 800 | 110 | 7 | |
25 | 1400 | 140 | 10.5 | 25 |
Some Michaelis-Menten type functions are eye-fitted to the above data. If c is the cytokine concentration in pg/ml, and x is the Aß concentration. We have that for TNF-a secretion the function is
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For IL-6 we found
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And for IL-12 we have
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There were some individual donor fluctuations in the amount of cytokine secretion when monocytes were stimulated with Aß1-42. Eight individual donors were investigated whose monocytes were treated with 2.5 µM of Aß1-42. In table 1 of Fiala's et al., we can compare the results. Again, concentrations were compared to those stimulated by the control media containing DMSO.
Aß1-42 with monocytes stimulate monocyte transmigrating across the BBB model:
The model consisted of placing a monolayer of human endothelial cells derived from cerebral microvessels and human astrocytes separating the vascular side (upper chamber) from the brain parenchymal side (lower chamber). In a control experiment, 5×105 human monocytes were placed. Figure 4 of Fiala's et al. paper shows that:
It has been strongly suggested that inflammation plays a pivotal role
in the pathogenesis of AD and development of dementia. In vitro cultures
of human microglia obtained from rapid autopsies from individuals with
AD secreted 100-fold or more IL-1b, IL-6 and
TNF-a than those cells from nondemented subjects.
In this study fluctuations in cytokine secretion elicited by Aß
in different donors are thought to be due to the individual's immunological
responsiveness. Also, in this study the authors show the proinflammatory
effects of Aß1-42 on peripheral monocytes. It is suggested
that some of the microglia-like cells surrounding the Aß fibrils
are transmigrated monocytes from the BBB. In a dose and time-dependent
manner, it was shown how Aß induced differentiation of monocytes
into macrophages, as well as some monocyte migration across the BBB.
Reference:
[1] Fiala M, Zhang L, Gan X, Sherry B, Taub D, Graves MC, Hama, S, Way D, Weinand M, Witte M, Lorton D, Kuo Y_M, Roher AE (1998). Amyloid-beta induces chemokine secretion and monocyte migration across human blood-brain barrier model. Molec Med 4: 480-489.Abstract