Distinct Effects of Aducanumab and Lecanemab on Intraneuronal Endogenous Aβ42 and Phosphorylated Tau in Alzheimer’s Disease Treatment

Abstract

AbstractIn the treatment of Alzheimer’s Disease (AD), two FDA-approved monoclonal antibodies, Aducanumab (Adu) and Lecanemab (LCN), exhibit significant differences in clinical benefits. By utilizing human-induced basal forebrain cholinergic neurons (BFCNs) derived from AD patient skin fibroblasts, we successfully recapitulated the natural endogenous neuropathologies of Aβ42 and Tau within just 21 days and revealed distinct intraneuronal effects of Adu and LCN. Both antibodies are internalized into BFCNs and localize with cytosolic Aβ42. However, LCN, selectively targeting Aβ42 oligomers and protofibrils, triggers TRIM21 pathway and significantly enhances autolysosome- and proteasome-mediated Aβ42 clearance, thereby leading to a marked reduction in phosphorylated Tau181 (pTau181) pathology. In contrast, the fibrillized Aβ42-selective Adu shows considerably weaker effects. This study not only reveals the unique intraneuronal actions of Adu and LCN but also provides a reliable and accessible human neuronal model for evaluating potential AD therapeutics, emphasizing the importance of intraneuronal pathology in the treatment of AD.