Combating multiple aetiologies of Alzheimer's disease to rescue behavioural deficits

Alzheimer's disease (AD) encompasses a range of intricate pathologies characterized by aberrant protein aggregation, atypical accumulation of metal ions, increased levels of reactive oxygen species (ROS), oxidative stress, neuroinflammation, and synaptic dysfunction. These collectively contribute to a decline in learning, memory, and cognitive abilities, broadly classified as dementia. AD accounting for most of the dementia cases remains a significant health challenge. Despite extensive research, therapeutic advancements for AD and other neurodegenerative diseases (NDDs) have achieved modest success. In this context, our study presents a hybrid drug design approach involving strategic and tactical repurposing of the structural and functional pharmacophores of current or failed drugs and biologically active compounds by integrating them into a single structural framework to concurrently target key pathological hallmarks viz., amyloid beta (Aβ), tau, metal ions, ROS, and neuroinflammation (NLRP3 inflammasome). The evaluation of in vitro and cellular models of Aβ, tau, and microglia highlights the efficacy of the fluoro-derivative DM4 in mitigating multiple etiological factors. DM4 exhibits excellent blood-brain barrier (BBB) permeability and biocompatibility. DM4 effectively reduced the amyloid burden, neuroinflammation, synaptic dysfunction, and neurodegeneration in the APP/PSEN1 transgenic AD mouse model. Behavioural assessments corroborated the rescue of learning and memory deficits, thereby presenting a viable strategy for the treatment of neurodegeneration and its associated cognitive decline.