Expression of mutant human tau protein drives synaptic loss in Caenorhabditis elegans

Abstract

AbstractBackgroundTau aggregation is associated with many neurodegenerative diseases, and inter‐neuronal neurofibrillary lesions composed of tau are a defining characteristic of various tauopathies, including Alzheimer’s disease. Additionally, mutations in human tau have been linked to several neurodegenerative disorders with varying phenotypic effects. How tau aggregation results in altered neuronal function is complex and not yet fully understood. Animal models are powerful tools to probe tau aggregation‐dependent phenotypes. However, they can take a long time to mature and give phenotypes, are created in different genetic backgrounds and can require death of the animal to visualize outcomes. Thus, new models that can avoid some of these issues can facilitate a better understanding of tauopathies.MethodWe have generated multiple lines of transgenic C. elegans expressing different variants of the longest isoform of human tau (htau40) in neurons to better understand how aggregation might cause subsequent downstream events leading to increased toxicity. We have used synaptic markers to examine the consequences of tau aggregation on synaptic integrity during aging.ResultWhen broadly expressed throughout the nervous system an aggregation prone htau40 variant (3PO) or an FTDP‐17 associated mutation (P301L) resulted in decreased lifespan, as well as a decreased locomotor capability as animals aged. Decreased lifespan, along with cognitive and motor defects, are associated with human tauopathies, suggesting our model is reproducing consequences relevant to human disorders. When we selectively express mutated htau40 in the GABAergic motorneurons, we find an age‐associated decline in the number of GABAergic motor neuron synapses, importantly, in the absence of other indicators of neuronal degeneration, i.e. axons and cell bodies were still intact. We have also begun testing mutations in C. elegans orthologs of known Alzheimer’s risk factors and found that loss of the LAR‐like receptor tyrosine phosphatase enhances the synaptic loss due to mutations in htau40.ConclusionC. elegans models of tauopathies permit an analysis of synaptic phenotypes in living animals. Our model can be used to probe both tau variants and other genetic modifiers to better understand how tau aggregation impacts neuronal homeostasis and function.