A glitazone-based chemical platform for mechanistic modulation of amyloid-β aggregation and associated pathology

Alzheimer's disease (AD) arises from intertwined pathological features, including amyloid-β (Aβ) aggregation, metal ion dyshomeostasis, oxidative stress, and cholinergic dysfunction, yet chemical strategies capable of interrogating and regulating these processes remain limited. Here, we identify glitazone derivatives as chemically tunable small molecules that modulate multiple AD-relevant pathways. Through intermolecular interactions, these compounds alter the aggregation behavior of both metal-free and metal-bound Aβ across distinct assembly stages, attenuating associated cytotoxicity. Integrated biophysical and chemical analyses reveal residue- and conformation-specific interactions between glitazone derivatives and Aβ, accompanied by metal-dependent oxidative modifications. In addition to aggregation control, selected glitazone derivatives exhibit antioxidant activity and acetylcholinesterase inhibition, enabling engagement of multiple pathological targets of AD. Collectively, this work establishes glitazones as a chemically tunable platform for mechanistic investigation and multi-target-directed modulation of amyloid pathology, providing a framework for probing interconnected biochemical processes underlying AD.