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Modeling Alzheimer's disease immune therapy mechanisms: Interactions of human postmortem microglia with antibody‐opsonized amyloid beta peptide
Author(s) -
Lue LihFen,
Walker Douglas G.
Publication year - 2002
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.10422
Subject(s) - microglia , opsonin , antibody , receptor , immunology , alzheimer's disease , phagocytosis , immune system , proinflammatory cytokine , inflammation , amyloid (mycology) , chemistry , biology , medicine , pathology , disease
The induction of an antibody response to amyloid beta (Aβ) peptide has become a strategy for the treatment of Alzheimer's disease (AD). This has proven effective in reducing the plaque burden in transgenic mice that develop Aβ plaques similar to human AD patients. The mechanism for enhanced clearance of Aβ is partly due to the interaction of immunoglobulin Fcγ receptor‐expressing microglia and specific antibody‐opsonized Aβ deposits. This interaction can stimulate Fcγ receptor‐mediated phagocytosis, but also results in inflammatory activation of these cells. Consequently, interaction of microglia with antibody‐antigen complexes could exacerbate the existing inflammation in the brains of AD patients. In this study, we used substrate‐bound Aβ and cultured human microglia from AD and non‐demented cases to model interaction of microglia and antibody‐opsonized plaques in AD brains. Enhanced production of tumor necrosis factor‐α, macrophage colony stimulating factor, interleukin‐10, and superoxide ions was detected. We also demonstrated enhanced uptake of opsonized Aβ by microglia, which was reduced significantly in the presence of excess IgG, indicative of the involvement of Fcγ receptor‐mediated mechanisms. Human microglia were shown in this study to express mRNA for Fcγ receptors I, IIa, IIb, and III. The expression of Fcγ receptor II was augmented by proinflammatory stimulation. These results suggest that initial interactions of human microglia with antibody‐opsonized amyloid could result in increased inflammation. The consequence of this on inflammatory pathology in AD brains needs to be considered before immunization is used as a strategy for treating AD. © 2002 Wiley‐Liss, Inc.