Biberoglu_2026_Drug.Dev.Res_87_e70330

ALZ-801, a valine-conjugated prodrug of tramiprosate, has recently been evaluated in a Phase III trial as a potential Alzheimer's disease (AD)-modifying therapy. Tramiprosate reduces misfolding of amyloid beta (Abeta) monomers and inhibits oligomer formation. In the present study, we investigated tramiprosate's effects on amyloidogenic processing of amyloid precursor protein (APP) and tau phosphorylation using the N2a-APPSwe cell line as a cellular model of AD. Tramiprosate decreased levels of secreted Abeta40 and Abeta42 in a dose-dependent manner without affecting cell viability. It also reduced the levels of APP, beta-site APP cleaving enzyme 1 (BACE1), and presenilin 1 C-terminal fragment (PS1-CTF) in this cellular model, indicating that tramiprosate may modulate amyloidogenic APP processing at multiple steps, thereby reducing Abeta production. Additionally, tramiprosate decreased tau phosphorylation at Ser202/Thr205 and Ser396/Ser404 in a dose-dependent manner while total tau level remained unchanged. Increased phosphorylation of glycogen synthase kinase-3beta (GSK-3beta) at Ser9, without altering total GSK-3beta levels, suggests that GSK-3beta inhibition underlies the decrease in tau phosphorylation at these sites. As a result, tramiprosate's impact on both amyloidogenic APP processing and tau phosphorylation reveals its potential to modify AD.