Aggregation‐prone human tau accelerates lifespan and motility decline in a Caenorhabditis elegans model of tau polymerization

Abstract

AbstractBackgroundTau aggregates is a key molecular hallmark of Alzheimer’s disease and other Alzheimer’s Disease‐Related Disorders. In these neurodegenerative disorders tau is aggregated in areas of the brain that exhibit high levels of synaptic and neuronal degeneration. Most animal models focus on neuronal death as is an apparent phenotype; however, we lack an in vivo model to observe the events that occur early in pathology compared to the endpoint (neuronal death). Thus, we want to build a model using C. elegans to understand the factors that initiate tau polymerization and toxicity.MethodTo this end, we have generated a transgenic C. elegans model expressing different variants of the longest human tau isoform (hTau40) tagged to GFP. We used a pan‐neuronal promoter to express wild‐type hTau40 and several aggregation‐prone hTau40 variants. We also used mutated alleles to test the conditions under which wild‐type tau is induced to aggregate or can exacerbate the phenotype observed under the aggregation‐prone tau variants. We used confocal microscopy to assess the accumulation of tau‐GFP within neurons in an age‐dependent manner. In addition, we used a combination of lifespan, behavior and biochemical assays to evaluate the role of tau‐GFP intensity/location with the overall healthspan of the nematode.ResultWe observed differences in the accumulation and presentation of tau variants can be measured in vivo using GFP. Wild‐type tau‐GFP appears smooth and filamentous and localized to axons and cell bodies. On the contrary, the aggregation‐prone 3PO‐tau is punctate in axons with extensive inclusions of GFP in cell bodies which increases in an age‐dependent manner. The expression of aggregation‐prone tau variants appears to correlate with the decreased lifespan and decreased motility, which is an indication that tau aggregation within the cell bodies is toxic.ConclusionThese results suggests that we can use our model to identify factors that can regulate tau aggregation in vivo. Additionally, the further development of this C. elegans model can be use to question early physiological changes that occur early vs. late in the disease while identifying or validating possible risks factors.