Abstract
Alzheimer's Disease (AD) is an age-related dementia and presents a growing medical and economic burden as the average human lifespan continues to rise. AD is classically diagnosed via the accumulation and aggregation of two major proteins: amyloid-β and tau. To date, potential and FDA-approved therapies designed to clear these aggregates at best delay rather than prevent disease, indicating that the root cause of AD lay upstream of aggregate formation. Tau protein's phosphorylation is critical for AD progression, and phosphorylation at Threonine 231 is thought to be an early disease-associated, "gatekeeper" event. Previously, we showed that genomic, single-copy insertion of phosphomimetic human tau (T231E) into C. elegans mechanosensory neurons induced age-dependent deficits in light-touch sensation. Herein, we have generated new C. elegans models which express pan-neuronal human tau to assess the idea of selective vulnerability and whether specific neuronal behaviors might be impacted preferentially. We also tested whether tau clearance via an Auxin Inducible Degron (AID) could reverse these deficits. Despite our hypothesis that prolonged stress in older animals would induce irreversible metabolic rewiring or maladaptation, tau depletion rescued known behavioral deficits at all ages tested, including in old worms which displayed the most overt phenotypes. Taken together, our data suggest that neuronal dysfunction induced by phosphorylated tau is reversible and provides reassurance that current early-phase therapeutic efforts aimed at reducing soluble tau levels in AD patients may prove effective.