Caenorhabditis elegans as a Model for Studying Nrf2/SKN-1 Activation in Alzheimer’s Disease: Plant Bioactive Compounds and Therapeutic Translation

Alzheimer’s disease (AD) is a neurodegenerative disorder, which is characterized by several features, such as the deposition of amyloid β (Aβ) fibrils in the brain, leading to the formation of plaques and secondly tau-associated neurofibrillary tangles, resulting in the degeneration of the brain cells. Another feature of AD is mitochondrial dysfunction and oxidative stress, which are linked to the excessive production of reactive oxygen species (ROS). Under physiological conditions, ROS homeostasis is well controlled by the ROS generating system and the cellular antioxidant network. This antioxidant network is in part controlled by nuclear factor erythroid 2-related factor 2 (Nrf2), and its activation protects tissues against oxidative stress and chronic inflammation. Since oxidative stress, inflammation, and impaired proteostasis are significantly involved in the pathogenesis of AD, the KEAP1-Nrf2 system has emerged as a promising therapeutic target for the disease. Caenorhabditis elegans is an invaluable model organism among others for neurodegenerative disease research, due to its short life cycle, transparent body, and fully mapped nervous system and many transgenic C. elegans models have been developed to study different aspects of AD. This review attempts to provide comprehensive understanding of the molecular characteristics and pathological basis of AD, including the altered Nrf2-ARE signaling in AD and the molecular architecture and regulation of the Nrf2-SKN-1 pathway in C. elegans. An overview of plant-derived natural products and their effect on Nrf2/SKN-1 activation. Several classical and novel transgenic strains are described, translating findings from C. elegans to mammalian models and humans, including clinical translations and ongoing trials, as well as personalized medicinal approaches are discussed.