Aβ antibodies target not only amyloid plaques but also distinct brain cells and vessels

BACKGROUND: Amyloid beta (Aβ) antibodies are the only therapies to slow cognitive decline in Alzheimer's disease (AD). Yet the sites where antibodies engage Aβ in the brain and mechanisms that lower Aβ are not fully understood. Defining Aβ antibody localizations in the brain is essential to understand how immunotherapy is beneficial for AD. METHODS: N-terminal Aβ antibody 6E10 was injected via three different routes into different AD mouse models. N-terminal Aβ antibodies were empirically shown as most effective in AD mice. Antibody localization was examined in the brain after injections. Glymphatic dynamics were also evaluated. RESULTS: As expected, Aβ antibody 6E10 bound to plaques but remarkably also localized to vulnerable neurons, such as hippocampal CA1 pyramidal cells, as well as microglia, astrocytes, oligodendrocytes, perivascular macrophages, and blood vessels. Antibodies did not alter glymphatic function. DISCUSSION: We provide detailed localizations of antibodies in AD mouse brains, offering insights into targets of Aβ antibody-based immunotherapy.