The basis of anti-Aβ antibody therapy: The toxicity of Aβ aggregates and the mechanism of action of anti-Aβ antibodies.

Abstract

In the pathophysiology of Alzheimer's disease (AD), the amyloid hypothesis, which posits that amyloid β-protein (Aβ) abnormally aggregates and damages neurons with tau, has been proposed. It was originally thought that the accumulation of insoluble amyloid fibrils in the brain leads to AD-inducing neurotoxicity; however, in recent years, the positioning of early and intermediate aggregates has also been emphasized. In particular, following the positive results of phase 3 clinical trials of lecanemab and its approval in Japan and the United States, the pathology of protofibrils, which are the target molecules of lecanemab, has attracted attention. Using high-speed atomic force microscopy, we have previously reported that lecanemab, which has a high affinity for protofibrils, binds to and surrounds them. Donanemab, a recombinant monoclonal antibody that primarily targets fibrils composed of N3pG Aβ, has also attracted attention because of its efficacy in phase 3 clinical trials in patients with early stage AD.