Neuroprotective Effects of CS-PLGA@Au Nanocomposites Against Amyloid-β aggregation and Oxidative Stress in In Vitro and In Vivo Models of Alzheimer’s Disease

Alzheimer’s disease (AD) features a range of pathological hallmarks that are multifactorial, including the buildup of amyloid-β (Aβ) plaques, neuronal cell death, oxidative stress, and dysfunctions in cholinergic and mitochondrial systems. In this study, the curcumin-functionalized chitosan–PLGA nanocomposite embedded with gold nanoparticles (CS-PLGA@AuNCs) was synthesized via co-precipitation to enhance targeted neuroprotection. Detailed physicochemical characterization using FT-IR, XRD, and HRTEM-EDX confirmed the successful creation, structural stability, and consistent morphology of CS-PLGA@AuNCs. In vitro studies using neuronal cell models showed excellent compatibility, effective cellular uptake, and a notable reduction in Aβ protein expression. CS-PLGA@AuNCs significantly reduced neuronal apoptosis and oxidative damage. Confocal microscopy further confirmed the downregulation of both Aβ and tau proteins, suggesting strong potential to alleviate AD-related pathological signaling. To assess in vivo effectiveness, we treated ICV-STZ-induced AD rats with CS-PLGA@AuNCs. Behavioral evaluations indicated enhanced learning and memory, supporting the compound’s neuroprotective function in reducing cognitive and synaptic deficits. Biochemical assessments revealed significant decreases in acetylcholinesterase (AChE) and malondialdehyde (MDA) levels, reflecting restored cholinergic function and reduced lipid peroxidation. Additionally, the activities of antioxidant enzymes, including SOD, CAT, and GPx, were substantially increased in the cortex and hippocampus, indicating enhanced internal defense mechanisms. The activities of mitochondrial complexes were also positively adjusted, suggesting improved cellular respiration and diminished mitochondrial dysfunction. Overall, these results underscore CS-PLGA@AuNCs as promising in multifunctional nanotherapy, capable of targeting critical features of AD. The findings support their potential for further preclinical development and eventual clinical application for the management of AD.