Antioxidant Natural Compounds Integrated with Targeted Protein Degradation: A Multi-Modal Strategy for Alzheimer's Disease Therapy.

Alzheimer's disease (AD) Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by protein aggregation, oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation, leading to cognitive decline. Current therapies remain largely symptomatic, highlighting the need for multi-target therapeutic strategies. Recent advances in antioxidant natural compounds and targeted protein degradation (TPD) technologies-particularly proteolysis-targeting chimeras (PROTACs), offer complementary mechanisms for disease modification. Natural antioxidants, including flavonoids, polyphenols, terpenoids, and alkaloids, confer neuroprotection by reducing reactive oxygen species, activating Nrf2 pathways, restoring mitochondrial function, and suppressing neuroinflammation. PROTACs, in contrast, selectively degrade pathological proteins such as hyperphosphorylated tau, amyloid-β, and APP fragments through the ubiquitin-proteasome system. The integrated "Antiox-PROTAC" approach combines these modalities to simultaneously mitigate oxidative stress and eliminate neurotoxic proteins. Natural compounds may act as warheads or scaffolds in PROTAC design, retaining antioxidant activity while enabling targeted degradation. Early preclinical findings demonstrate synergistic neuroprotective potential, though translational challenges remain, including blood-brain barrier permeability, bioavailability, and delivery optimization. Future directions involve hybrid molecules, nanoparticle-based delivery, and personalized therapeutic strategies. Overall, the Antiox-PROTAC paradigm represents a next-generation, multi-modal framework with the potential to modify disease progression and enhance cognitive outcomes in Alzheimer's disease.