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

Background: Aside from numerous parenchymal and vascular deposits of amyloid β (Aβ) 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 Aβ 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 Aβ 1-42 on the brain side of the blood-brain barrier model. Results: In cultures of peripheral monocytes, Aβ 1-42 induced the secretion of proinflammatory cytokines TNF-a, IL-6, IL-1β, and IL-12, as well as CC chemokines MCP-1, MIP-1α, and MIP-1β, and CXC chemokine IL-8 in a dose- related fashion. In the blood-brain barrier model, Aβ 1-42 and monocytes on the brain side potentiated monocyte transmigration from the blood side to the brain side. Aβ 1-42 stimulated differentiation of monocytes into adherent macrophages in a dose-related fashion. The magnitude of these proinflammatory effects of Aβ 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.