Lecanemab promotes Fc receptor-dependent cell-mediated internalization and degradation of aggregated amyloid-beta in vitro and ex vivo.

Plaque deposits containing aggregated amyloid beta peptide (Aβ) fibrils are present in brain regions affected by Alzheimer's disease (AD). Lecanemab is a therapeutic monoclonal antibody that binds preferentially to soluble Aβ assemblies known as protofibrils, as well as to aggregated Aβ in amyloid plaques. Administration of lecanemab to individuals with early-stage AD reduces plaque burden and slows cognitive decline. The present study explored the role of immune cells in the mechanism of action of lecanemab using confocal microscopy, flow cytometry, and immunoassays. We show that lecanemab increases the internalization of synthetic Aβ42 protofibrils by human monocytic and mouse microglial cells, and that this effect is Fc gamma receptor-dependent. The Aβ42 protofibrils taken up by these cells were subsequently degraded within lysosomes. To investigate immune cell involvement in a system that resembled the clinical situation more closely, we evaluated the involvement of lecanemab in the removal of plaque pathology from sections of postmortem AD brain by primary human macrophages. Our results confirm that the lecanemab-mediated decrease in plaque pathology requires the presence of immune cells and is Fc gamma receptor-dependent. These data support the hypothesis that lecanemab's clinical effects involve Fc gamma receptor-dependent immune cell-mediated internalization and lysosomal degradation of Aβ protofibrils and plaques.