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Amyloid-beta induces chemokine secretion and monocyte migration across a human blood--brain barrier model
1Department of Medicine, UCLA School of Medicine, Los Angeles, California, USA. fiala@ucla.edu
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.
Insights
Alzheimer's disease involves brain inflammation. Amyloid beta peptide triggers monocytes to secrete inflammatory chemicals and cross the blood-brain barrier, potentially worsening brain damage in some patients.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Alzheimer's disease (AD) pathology includes amyloid beta (A beta) deposits, neurofibrillary tangles, and neuronal loss.
- A chronic inflammatory response, marked by microglial activation, is also characteristic of AD.
- Altered blood-brain barrier (BBB) permeability and chemotaxis can facilitate peripheral cell infiltration into the brain.
Purpose of the Study:
- To investigate the role of human monocytes in Alzheimer's disease-related inflammation.
- To examine the effects of amyloid beta (A beta) on monocyte differentiation and cytokine/chemokine secretion.
- To assess monocyte transmigration across a human blood-brain barrier model in response to A beta.
Main Methods:
- Human peripheral monocytes were cultured with A beta 1-42 to assess cytokine and chemokine production.
- A human blood-brain barrier model using brain endothelial and astroglial cells was established.
- Monocyte transmigration across the BBB model was evaluated when challenged with A beta 1-42.
Main Results:
- A beta 1-42 dose-dependently induced secretion of pro-inflammatory cytokines (TNF-alpha, IL-6, IL-1 beta, IL-12) and chemokines (MCP-1, MIP-1 alpha, MIP-1 beta, IL-8) by monocytes.
- A beta 1-42 promoted monocyte differentiation into macrophages.
- Monocyte transmigration across the BBB model was enhanced by A beta 1-42 and monocytes on the brain side.
- Donor variability significantly influenced the magnitude of A beta 1-42's pro-inflammatory effects.
Conclusions:
- Circulating monocytes/macrophages can infiltrate the brain in Alzheimer's disease.
- Recruitment by chemokines may lead these peripheral cells to contribute to neuroinflammation and brain damage.
- Individual responses to A beta vary, impacting the inflammatory contribution of monocytes/macrophages.