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Activation of human macrophages by amyloid-beta is attenuated by astrocytes
H A Smits1, A J van Beelen, N M de Vos
1Eijkman-Winkler Institute for Microbiology, Infectious Diseases and Inflammation, Section of Neuroimmunology, University Medical Center Utrecht, Room G04.614, Heidelberglaan 100, NL-3584 CX Utrecht, The Netherlands. h.a.smits@lab.azu.nl
Abstract:
In Alzheimer's disease, neuritic amyloid-beta plaques along with surrounding activated microglia and astrocytes are thought to play an important role in the inflammatory events leading to neurodegeneration. Studies have indicated that amyloid-beta can be directly neurotoxic by activating these glial cells to produce oxygen radicals and proinflammatory cytokines. This report shows that, using primary human monocyte-derived macrophages as model cells for microglia, amyloid-beta(1-42) stimulate these macrophages to the production of superoxide anions and TNF-alpha. In contrast, astrocytes do not produce both inflammatory mediators when stimulated with amyloid-beta(1-42). In cocultures with astrocytes and amyloid-beta(1-42)-stimulated macrophages, decreased levels of both superoxide anion and TNF-alpha were detected. These decreased levels of potential neurotoxins were due to binding of amyloid-beta(1-42) to astrocytes since FACScan analysis demonstrated binding of FITC-labeled amyloid-beta(1-42) to astrocytoma cells and pretreatment of astrocytes with amyloid-beta(1-16) prevented the decrease of superoxide anion in cocultures of human astrocytes and amyloid-beta(1-42)-stimulated macrophages. To elucidate an intracellular pathway involved in TNF-alpha secretion, the activation state of NF-kappaB was investigated in macrophages and astrocytoma cells after amyloid-beta(1-42) treatment. Interestingly, although activation of NF-kappaB could not be detected in amyloid-beta-stimulated macrophages, it was readily detected in astrocytoma cells. These results not only demonstrate that amyloid-beta stimulation of astrocytes and macrophages result in different intracellular pathway activation but also indicate that astrocytes attenuate the immune response of macrophages to amyloid-beta(1-42) by interfering with amyloid-beta(1-42) binding to macrophages.
Insights
Alzheimer's disease involves amyloid-beta plaques activating immune cells. Astrocytes can reduce harmful inflammation by binding amyloid-beta, thus protecting against neurodegeneration.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Alzheimer's disease (AD) pathogenesis involves neuroinflammation driven by amyloid-beta plaques.
- Activated microglia and astrocytes are implicated in AD-related neurodegeneration.
- Amyloid-beta may directly induce neurotoxicity by activating glial cells.
Purpose of the Study:
- To investigate the differential responses of macrophages (modeling microglia) and astrocytes to amyloid-beta(1-42).
- To determine the role of astrocytes in modulating the inflammatory response to amyloid-beta in co-cultures.
- To elucidate intracellular pathways involved in tumor necrosis factor-alpha (TNF-alpha) secretion.
Main Methods:
- Primary human monocyte-derived macrophages and astrocytoma cells were used as models.
- Cells were stimulated with amyloid-beta(1-42) and amyloid-beta(1-16).
- Production of superoxide anions and TNF-alpha was measured.
- Amyloid-beta binding to astrocytes was assessed using FITC-labeled amyloid-beta and FACScan analysis.
- Nuclear factor-kappa B (NF-kappaB) activation was investigated.
Main Results:
- Amyloid-beta(1-42) stimulated macrophages to produce superoxide anions and TNF-alpha.
- Astrocytes did not produce these inflammatory mediators when stimulated with amyloid-beta(1-42).
- Co-cultures of astrocytes and amyloid-beta-stimulated macrophages showed decreased superoxide anion and TNF-alpha levels.
- Amyloid-beta(1-42) binding to astrocytes was confirmed, and this binding reduced inflammatory mediator production by macrophages.
- NF-kappaB activation was observed in astrocytoma cells but not in amyloid-beta-stimulated macrophages.
Conclusions:
- Astrocytes and macrophages exhibit distinct intracellular pathway activation in response to amyloid-beta.
- Astrocytes attenuate the inflammatory response of macrophages to amyloid-beta(1-42) by binding it.
- This astrocyte-mediated suppression of inflammation suggests a protective role in Alzheimer's disease.