A Novel Copper Chelator Reverses Neuropathology and Improves Cognition in an Alzheimer's Disease Model

This study investigated the potential of novel copper chelators as disease-modifying agents for Alzheimer's disease (AD), focusing on copper dyshomeostasis, a key pathogenic factor in AD that contributes to amyloid-beta (Aβ) aggregation. A series of nine novel imine-based compounds were synthesized and characterized. Their therapeutic efficacy was evaluated through a comprehensive pipeline, beginning with in silico ADME predictions indicating blood-brain barrier permeability and oral bioavailability. In vitro assays using EPR demonstrated the ability of the compounds to extract copper from the Cu-Aβ. In cellular studies using hippocampal cells (mHippoE-2), 2 compounds exhibited low cytotoxicity and significant neuroprotection against Aβ-induced lipid peroxidation and DNA damage. In vivo validation in the streptozotocin (STZ)-induced rat model of AD revealed that administration of one of the compounds significantly improved spatial memory. Furthermore, one compound substantially increased the expression of BDNF, validating the therapeutic strategy of targeting copper dyshomeostasis in the treatment of Alzheimer's disease.