Age-dependent SKN-1/NRF cytoprotection at the cost of metabolic homeostasis

补编摘要

ABSTRACT OF SUPPLEMENT New approaches are needed to combat Alzheimer’s disease (AD), a neurodegeneration condition that affects millions of people in the United States at an estimated cost exceeding hundreds of billions of dollars. Despite decades of work a treatment does not exist. As such, the need for new models to accelerate our understanding of this debilitating disease are needed – but development of these models takes time. We propose using the well-established C. elegans model of AD to interrogate new models of AD pathology. Previously, our lab discovered a critical link for the cytoprotective transcription factors SKN-1 (in worms) and NRF2 (in mammals) for maintaining metabolic homeostasis in a diet-dependent manner. Moreover, we recently published that SKN-1 mediates one of the earliest responses to pathogen exposure. The “pathogen hypothesis” is an understudied idea that chronic infection by viral, bacterial, and/or fungal pathogens can be a potent contributor for sporadic AD onset during aging. In light of the high degree of conservation of SKN-1/NRF stress pathway responses in worms, mice, and humans that we have documented, we hypothesize that: (1) SKN-1/NRF2 is the central mediator of the “pathogen hypothesis” models of Alzheimer’s Disease; and (2) Diet-gene pairs influence AD pathology progression and severity. We focus by on our established gene and diet combinations in the context of well-established AD models as well as new paradigms that integrate pathogen exposure and responses on AD pathology. This project will engage a team of scientists to test novel and easily testable models of the pathogen hypothesis in C. elegans (Aim 1) and the impact of diet on AD markers (Aim 2). Together, this supplement will address the significance of two environmental conditions (pathogen exposure and diet) on established and novel AD models in C. elegans. Capitalizing on the facile genetic and molecular approaches, a sort generation time, and ease of culturing, C. elegans is the ideal model for this one-year administrative supplement project to rapidly acquire large data sets and integrate these findings into new studies of AD pathology in mammals. The results of these efforts will lead to new therapeutic approaches to treat AD.