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. 1998 Jul;4(7):480–489.

Amyloid-beta induces chemokine secretion and monocyte migration across a human blood--brain barrier model.

M Fiala 1, L Zhang 1, X Gan 1, B Sherry 1, D Taub 1, M C Graves 1, S Hama 1, D Way 1, M Weinand 1, M Witte 1, D Lorton 1, Y M Kuo 1, A E Roher 1
PMCID: PMC2230332  PMID: 9713826

Abstract

BACKGROUND: Aside from numerous parenchymal and vascular deposits of amyloid beta (A beta) peptide, neurofibrillary tangles, and neuronal and synaptic loss, the neuropathology of Alzheimer's disease is accompanied by a subtle and chronic inflammatory reaction that manifests itself as microglial activation. However, in Alzheimer's disease, alterations in the permeability of the blood-brain barrier and chemotaxis, in part mediated by chemokines and cytokines, may permit the recruitment and transendothelial passage of peripheral cells into the brain parenchyma. MATERIALS AND METHODS: Human monocytes from different donors were tested for their capacity to differentiate into macrophages and their ability to secrete cytokines and chemokines in the presence of A beta 1-42. A paradigm of the blood-brain barrier was constructed utilizing human brain endothelial and astroglial cells with the anatomical and physiological characteristics observed in vivo. This model was used to test the ability of monocytes/macrophages to transmigrate when challenged by A beta 1-42 on the brain side of the blood-brain barrier model. RESULTS: In cultures of peripheral monocytes, A beta 1-42 induced the secretion of proinflammatory cytokines TNF-alpha, IL-6, IL-1 beta, and IL-12, as well as CC chemokines MCP-1, MIP-1 alpha, and MIP-1 beta, and CXC chemokine IL-8 in a dose-related fashion. In the blood-brain barrier model, A beta 1-42 and monocytes on the brain side potentiated monocyte transmigration from the blood side to the brain side. A beta 1-42 stimulated differentiation of monocytes into adherent macrophages in a dose-related fashion. The magnitude of these proinflammatory effects of A beta 1-42 varied dramatically with monocytes from different donors. CONCLUSION: In some individuals, circulating monocytes/macrophages, when recruited by chemokines produced by activated microglia and macrophages, could add to the inflammatory destruction of the brain in Alzheimer's disease.

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Selected References

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