Aβ Antibodies Target Not Only Amyloid Plaques But Also Distinct Brain Cells And Vessels

Abstract

BackgroundAntibodies against amyloid-{beta} (A{beta}) are the only therapies capable of slowing cognitive decline and reducing A{beta} plaque burden in Alzheimers disease (AD). Yet the precise sites where antibodies engage A{beta} in the brain, and the mechanisms that drive A{beta} clearance, are not fully defined. Defining the A{beta} antibody engagement with A{beta} in brain is essential to understand how immunotherapy can be beneficial for AD. MethodsWe administered the well-establsihed N-terminal A{beta} antibody 6E10 via intrahippocampal (IH), cisterna magna (CM), or intraperitoneal (IP) injection in AD mouse models. N-terminal A{beta} antibodies were seen as most effective in AD mouse models. Antibody 6E10 was not only assessed in A{beta} plaques, but also examined in association with diverse brain cells and vascular compartments. Glymphatic dynamics were evaluated following A{beta} antibody treatment. ResultsAs expected, A{beta} antibody 6E10 bound to A{beta} plaques but remarkably also localized to vulnerable neurons, such as hippocampal CA1 pyramidal cells, as well as microglia, astrocytes, oligodendrocytes, perivascular macrophages (PVMs), and blood vessels. Glymphatic function showed no significant alterations after antibody administration. ConclusionsA{beta} antibodies distribute not only to amyloid plaques but also to neurons, glial cells, and blood vessels. This study provides detailed localizations of antibody in the AD brain, offering valuable insights into cellular targets and spatial dynamics of A{beta} antibody-based immunotherapy.