ABSTRACT INVESTIGATION OF NEURODEGENERATIVE TAUOPATHIES USING CAENORHABDITIS ELEGANSByDerek Vonarx Neurodegenerative tauopathies are a class of neurodegenerative disease characterized by the accumulation of tau protein into neurofibrillary tangles in the human brain. Alzheimer’s disease (AD) is one such tauopathy. Until recently, the amyloid β hypothesis, suggesting that accumulation of amyloid β, was the leading hypothesis explaining cognitive decline in Alzheimer’s disease patients. However, treatments that reduce amyloid β levels in the brain, such as aducanumab, have shown limited efficacy, and therefore, the role of tauopathy and the potential synergistic relationship of tau and amyloid β requires further study to understand the mechanism of cognitive decline in AD. One of the many difficulties of studying AD is that cognitive symptoms are not observed until late in life. Because of the late onset of symptoms, modelling AD in mammals is expensive and time consuming. To circumvent these issues, a nematode, C. elegans, model was developed because C. elegans have a short lifespan of three weeks, can be genetically modified to express human tau, and are inexpensive to maintain. A genetically modified C. elegans strain (eat-4::GFP; aex-3::tau) expressing both human tau in all neurons and green fluorescent protein in glutamatergic neurons was developed. It was found that the novel strain exhibits neurodegeneration that can be rescued by supplementation with the epoxide hydrolase inhibitor, 12-[[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino]-dodecanoic acid (AUDA), through an unknown mechanism. This novel strain serves as a useful model to study the mechanism of Alzheimer’s disease cognitive decline as C. elegans have a relatively short lifespan that allows for extensive therapeutic and genetic screening.
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