Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer's disease

TLDR

Active immunization with amyloid beta reduces brain deposition in transgenic mouse models, and peripherally administered anti‑Aβ antibodies can mimic this effect. The study aims to determine whether the monoclonal antibody m266, which targets the central domain of Aβ, can alter Aβ metabolism and clearance by sequestering plasma Aβ. The authors employed m266, a monoclonal antibody that binds and sequesters plasma Aβ, to investigate its impact on CNS–plasma Aβ equilibrium. Peripheral administration of m266 in PDAPP mice produced a 1,000‑fold increase in plasma Aβ, markedly reduced brain Aβ deposition without binding brain plaques, and thus lowered brain burden by shifting CNS–plasma Aβ clearance.

Abstract

Active immunization with the amyloid beta (A beta) peptide has been shown to decrease brain A beta deposition in transgenic mouse models of Alzheimer's disease and certain peripherally administered anti-A beta antibodies were shown to mimic this effect. In exploring factors that alter A beta metabolism and clearance, we found that a monoclonal antibody (m266) directed against the central domain of A beta was able to bind and completely sequester plasma A beta. Peripheral administration of m266 to PDAPP transgenic mice, in which A beta is generated specifically within the central nervous system (CNS), results in a rapid 1,000-fold increase in plasma A beta, due, in part, to a change in A beta equilibrium between the CNS and plasma. Although peripheral administration of m266 to PDAPP mice markedly reduces A beta deposition, m266 did not bind to A beta deposits in the brain. Thus, m266 appears to reduce brain A beta burden by altering CNS and plasma A beta clearance.