Simultaneous neuronal expression of human amyloid-ß and Tau genes drives global phenotypic and multi-omic changes in C. elegans.

Alzheimer's disease and Alzheimer's related diseases (ADRD) are a class of prevalent age-related neurodegenerative disorders characterized by the accumulation of amyloid- ß (Aß) plaques and Tau neurofibrillary tangles. The intricate interplay between Aß and Tau proteins requires further investigation to better understand the precise mechanisms underlying disease pathology. The nematode Caenorhabditis elegans ( C. elegans ) serves as an invaluable model organism for studying aging and neurodegenerative diseases. Here we performed an unbiased systems analysis of a C. elegans strain expressing both Aß and Tau proteins within neurons. Intriguingly, even at an early stage of adulthood, we observed reproductive impairments and mitochondrial dysfunction consistent with substantial disruptions in mRNA transcript abundance, protein solubility, and metabolite levels. Notably, the simultaneous expression of these two neurotoxic proteins exhibited a synergistic effect, leading to accelerated aging in the model organism. Our comprehensive findings shed new light on the intricate relationship between normal aging processes and the etiology of ADRD. Specifically, we demonstrate the alterations to metabolic functions precede age-related neurotoxicity, offering critical insights into potential therapeutic strategies.