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Amyloid-β Induces Chemokine Secretion and Monocyte Migration across a Human Blood-Brain Barrier Model

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Abstract

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-α, 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.

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Acknowledgments

We thank Manuel B. Graber for critical reading of the manuscript and MaryAnn Ackers and Harry V. Vinters for examination of the model by transmission electron microscopy.

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Authors and Affiliations

  1. Department of Medicine, UCLA School of Medicine, Los Angeles, California, USA

    Milan Fiala & Suzan Hama

  2. Department of Neurology, UCLA School of Medicine, 710 Westwood Plaza, Los Angeles, California, 90095-1769, USA

    Ling Zhang, **aohu Gan & Michael C. Graves

  3. The Picower Institute, Manhasset, New York, USA

    Barbara Sherry

  4. National Institute on Aging, Baltimore, Maryland, USA

    Dennis Taub

  5. Department of Surgery, University of Arizona, Tucson, Arizona, USA

    Dennis Way, Martin Weinand & Marlys Witte

  6. Haldeman Laboratory for Alzheimer Disease Research, Sun Health Research Institute, Sun City, Arizona, USA

    Diane Lorton, Yu-Min Kuo & Alex E. Roher

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  1. Milan Fiala
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  3. **aohu Gan
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Correspondence to Milan Fiala.

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Communicated by R. Bucala.

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Fiala, M., Zhang, L., Gan, X. et al. Amyloid-β Induces Chemokine Secretion and Monocyte Migration across a Human Blood-Brain Barrier Model. Mol Med 4, 480–489 (1998). https://doi.org/10.1007/BF03401753

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