Tau clearance reverses touch neuron dysfunction in both young and aged.

Abstract

BackgroundAlzheimer's disease (AD) is an age-related dementia and presents a growing medical and economic burden. AD is classically diagnosed via the accumulation and aggregation of amyloid-β and tau. 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.ObjectivePreviously, we showed that genomic, single-copy insertion of phosphomimetic human tau (T231E) intomechanosensory neurons induced age-dependent deficits in light-touch sensation. Herein, we aimed to determine whether T231E tau could preferentially impact unique neuronal subclasses and whether observed deficits could be reversed via tau clearance.MethodsWe generated novelmodels which express pan-neuronal human tau tagged with an auxin inducible degron and utilized an assortment of behavioral assays to assess whether specific neuronal behaviors might be impacted preferentially and whether any observed deficits could be reversed with age.ResultsDespite our hypothesis that prolonged stress in older animals would induce irreversible metabolic rewiring or maladaptation, tau depletion rescued deficits in the behavioral response to light touch at all ages tested, including in old worms which displayed the most overt phenotypes.ConclusionsOur data suggests thatmechanosensory neurons are preferentially impacted by T231E, and that neuronal dysfunction induced by phosphorylated tau is reversible. This provides reassurance that current therapeutic efforts aimed at reducing soluble tau levels may prove effective.