Sporadic Alzheimer’s Disease (AD) is the most common form of dementia, and its severity is characterized by the progressive formation of tau neurofibrillary tangles along a well-described path through the brain. This spatial progression provides the basis for Braak staging of the pathological progression for AD. Tau protein is a necessary component of AD pathology, and recent studies have found that soluble tau species with selectively, but not extensively, modified epitopes accumulate along the path of disease progression before AD-associated insoluble aggregates form. As such, modified tau may represent a key cellular stressing agent that potentiates selective vulnerability in susceptible neurons during AD progression. Specifically, studies have found that tau phosphorylated at sites such as T181, T231, and S396 may initiate early pathological changes in tau by disrupting proper tau localization, initiating tau oligomerization, and facilitating tau accumulation and extracellular export. Thus, this review elucidates potential mechanisms through which tau post-translational modifications (PTMs) may simultaneously serve as key modulators of the spatial progression observed in AD development and as key instigators of early pathology related to neurodegeneration-relevant cellular dysfunctions.

Accumulation of inappropriately phosphorylated tau into neurofibrillary tangles is a defining feature of Alzheimer’s disease, with Tau pT231 being an early harbinger of tau pathology. Previously, we demonstrated that expressing a single genomic copy of human phosphomimetic mutant tau (T231E) in Caenorhabditis elegans drove age-dependent neurodegeneration. A critical finding was that T231E, unlike wild-type tau, completely and selectively suppressed oxidative stress-induced mitophagy. Here, we used dynamic imaging approaches to analyze T231E-associated changes in mitochondria and mitolysosome morphology, abundance, trafficking, and stress-induced mitophagy as a function of mitochondrial fission mediator dynamin-related protein 1, which has been demonstrated to interact with hyper phosphorylated tau and contribute to Alzheimer’s disease pathogenesis, as well as Pink1, a well-recognized mediator of mitochondrial quality control that works together with Parkin to support stress-induced mitophagy. T231E impacted both mitophagy and mitolysosome neurite trafficking with exquisite selectivity, sparing macroautophagy as well as lysosome and autolysosome trafficking. Both oxidative-stress-induced mitophagy and the ability of T231E to suppress it were independent of drp-1, but at least partially dependent on pink-1. Organelle trafficking was more complicated, with drp-1 and pink-1 mutants exerting independent effects, but generally supported the idea that the mitophagy phenotype is of greater physiologic impact in T231E. Collectively, our results refine the mechanistic pathway through which T231E causes neurodegeneration, demonstrating pathologic selectivity for mutations that mimic tauopathy-associated post-translational modifications, physiologic selectivity for organelles that contain damaged mitochondria, and molecular selectivity for dynamin-related protein 1-independent, Pink1-dependent, perhaps adaptive, and mitophagy.

Alzheimer’s disease (AD) is a complex neurodegenerative disorder that is classically defined by the extracellular deposition of senile plaques rich in amyloid-beta (Aβ) protein and the intracellular accumulation of neurofibrillary tangles (NFTs) that are rich in aberrantly modified tau protein. In addition to aggregative and proteostatic abnormalities, neurons affected by AD also frequently possess dysfunctional mitochondria and disrupted mitochondrial maintenance, such as the inability to eliminate damaged mitochondria via mitophagy. Decades have been spent interrogating the etiopathogenesis of AD, and contributions from model organism research have aided in developing a more fundamental understanding of molecular dysfunction caused by Aβ and toxic tau aggregates. The soil nematode C. elegans is a genetic model organism that has been widely used for interrogating neurodegenerative mechanisms including AD. In this review, we discuss the advantages and limitations of the many C. elegans AD models, with a special focus and discussion on how mitochondrial quality control pathways (namely mitophagy) may contribute to AD development. We also summarize evidence on how targeting mitophagy has been therapeutically beneficial in AD. Lastly, we delineate possible mechanisms that can work alone or in concert to ultimately lead to mitophagy impairment in neurons and may contribute to AD etiopathology.

Background: Alzheimer'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. Objective: 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 aimed to determine whether T231E tau could preferentially impact unique neuronal subclasses and whether observed deficits could be reversed via tau clearance. Methods: We generated novel C. elegans models 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. Results: Despite 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. Conclusions: Our data suggests that C. elegans mechanosensory 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.

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.

Tau protein accumulates myriad post-translational modifications as Alzheimer’s disease (AD) progresses, and early-disease tau modifications such as phosphorylation at threonine 231 (T231) likely play a key role in AD pathogenesis. Here, a series of “tunable tau” strains was developed in C. elegans to test the relative impact of tau pseudo-phosphorylation of T231 (T231E) compared to protein expression level as a driver of phenotypic penetrance and severity. Multiple copies of a cassette coding for pan-neuronal wildtype tau or T231E were inserted at a genomic safe harbor loci to create a repertoire of strains expressing tau from low to high levels. In stereotypical behavioral assays of locomotory activity, T231E selectively impacted phenotypic severity compared to wild-type human tau controls, which further tracked with age and tau expression level. However, deficits in associative memory were non-selective between tau and T231E. Moreover, genetic, pharmacologic, and molecular approaches indicated that mitophagy modulation could suppress T231E phenotypes. Additionally, a robust mitochondrial unfolded protein response (UPRmt) occurred in T231E, and loss of atfs-1 , a transcription factor central to the UPRmt suppressed T231E toxicity. These results demonstrate that phenotypic severity is invariably associated with tau dosage, while early-AD relevant modifications can be causative drivers of selective deficits. Consistent with recent findings, enhancing mitophagy or suppressing potentially maladaptive consequences of persistent UPRmt induction can be beneficial. This provides a solid foundation for further interrogation into mitochondrial quality control disruption as a potential root cause for AD pathogenesis. Highlights: Matched sets of pan-neuronal, multi-copy tau strains enhance experimental control Phosphomimetic tau elicits selective behavioral and neuronal dysfunction Phosphomimetic tau triggers a unique mitochondrial unfolded response Tau depletion and mitochondrial interventions rescue observed deficits Visual