Human serum albumin-3-amino-1-propanesulfonic acid conjugate inhibits amyloid-β aggregation and mitigates cognitive decline in Alzheimer's disease

Alzheimer's disease (AD) is the most commonly occurring brain disorder, characterized by the accumulation of amyloid-β (Aβ) and tau, subsequently leading to neurocognitive decline. 3-Amino-1-propanesulfonic acid (TPS) and its prodrug, currently under clinical trial III, serve as promising therapeutic agents targeting Aβ pathology by specifically preventing monomer-to-oligomer formation. Inspired by the potency of TPS prodrug, we hypothesized that conjugating TPS with human serum albumin (HSA) could enhance brain delivery and synergistically inhibit Aβ aggregation in mild to moderate AD. Thus, we prepared and extensively characterized HSA-TPS (h-TPS) conjugate using an eco-friendly coupling method. In vitro studies on Aβ aggregation kinetics and AFM imaging revealed significant prevention of Aβ aggregation. Additionally, h-TPS significantly reduced Aβ-induced neurotoxicity and H₂O₂-mediated reactive oxygen species (ROS) stress in SH-SY5Y cells. Moreover, h-TPS administration improved blood-brain barrier permeability and cellular uptake into neuronal cells as well as showed in vivo uptake inside the brain within 1 h. In vivo studies using an Aβ_1–42-induced acute AD rat model exhibited a dose-dependent significant reduction in hippocampal Aβ levels and restoration of declined spatial learning and memory with h-TPS treatment. Overall, findings suggest that h-TPS conjugate might be a promising neuroprotective agent for preventing Aβ aggregation in mild to moderate AD.