The Role of Microglia in Antibody-Mediated Clearance of Amyloid-Beta from the Brain

Dave      Morgan

Abstract

Immunotherapy has emerged as a leading new approach to the reduction of amyloid deposits in the brains of Alzheimer patients. At least 4 distinct actions of anti-Aß antibodies have been proposed as contributing to the inhibition of amyloid deposition and its clearance. Critically, each of these proposed mechanisms may be acting simultaneously, and it is feasible that different antibodies may utilize each mechanism to a different extent. One of these proposed mechanisms involves the activation of microglia and the phagocytosis of Aβ peptide. In general this is assumed to proceed through the Fcγ-receptor binding by antibody opsonized Aβ aggregates, however modifying the microglial phenotype into one with a greater propensity for phagocytosing Aβ is also feasible, as microglia avidly phagocytose Aβ in vitro without antibody present. Evidence is presented supporting arguments that microglial activation does play a role in amyloid removal, particularly compacted amyloid deposits, under certain conditions. In addition to the specific antibody used, other considerations in comparing different reports of antibody action in APP mice include the age of the mice, the extent of pre-existing amyloid when therapy is initiated, the time point when the effects of the therapy are examined and the route of antibody administration. Future questions will consider the source of the activated microglia near the plaques after antibody administration (resident or peripheral) and the extent to which shifts in the microglial phenotype mediate some of the amyloid lowering actions of immunotherapy.

Keywords: Immunotherapy, Microglia, Alzheimer patients, Aβ peptide, phagocytosing

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