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

In the treatment of Alzheimers 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 A{beta}42 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 A{beta}42. However, LCN, selectively targeting A{beta}42 oligomers and protofibrils, triggers TRIM21 pathway and significantly enhances autolysosome- and proteasome-mediated A{beta}42 clearance, thereby leading to a marked reduction in phosphorylated Tau181 (pTau181) pathology. In contrast, the fibrillized A{beta}42-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.