Synergistic Neuroprotective Drug Combinations Targeting Amyloid-Beta Toxicity in Caenorhabditis elegans: A Multitarget Approach for Alzheimer’s Disease

Abstract

A progressive neurodegenerative disease, Alzheimer’s disease (AD) is characterized by a multifactorial pathology that includes neuronal loss, oxidative stress, amyloid-beta (Aβ) accumulation, and mitochondrial dysfunction. Since currently available drugs like donepezil simply reduce symptoms, there is an urgent need for more potent, disease-modifying therapy. Using Caenorhabditis elegans (C. elegans) models of AD, we examined the treatment effectiveness of three novel antioxidant-based medication combinations: N-acetylcysteine + Curcumin (NAC+CUR), Mitoquinone + Butylated Hydroxyanisole (MitoQ+BHA), and Carnosine + Kynurenic Acid (CAR+KYNA). Phenotypic investigation was conducted using the wild-type N2 and transgenic CL4176 strains, the latter of which expresses human Aβ1–42 in muscle tissue. The Chou–Talalay approach was used for evaluating drug interactions in order to identify synergistic combinations. Lifespan, healthspan, Aβ-induced paralysis, stress tolerance, chemotaxis index, and fluorescence microscopy-measured amyloid burden were important outcomes. These results show that, in comparing with untreated and donepezil-M treated controls, all three drug combinations show synergistic interactions and significantly enhance physiological outcomes.