Aidan Kenny, Félix Hernández, Jesús Avila, José J Lucas, David C Henshall, Jochen HM Prehn, Eva M Jiménez-Mateos, and Tobias Engel
Tauopathies are a group of neurodegenerative diseases characterized by the pathological aggregation of the microtubule-associated protein tau. These include more than 20 diseases, with Alzheimer’s disease being the most frequent. While pathological and neurotoxic effects of tau are well documented, the mechanisms by which tau can promote neurodegeneration are less clear. Increasing evidence suggests a functional role for microRNAs in the pathogenesis of tauopathies, with altered expression and function of microRNAs in experimental models and patient brain. To determine whether a pathological expression of tau leads to altered microRNA expression, we investigated a mouse model (VLW), which overexpresses tau carrying three mutations identified in patients suffering from frontotemporal dementia with parkinsonism-17. Argonaute-2-bound microRNAs were co-immunoprecipitated using hippocampal tissue to identify active microRNAs within the model and quantified using a genome-wide high-throughput qPCR-based microRNA platform. While similar numbers of microRNAs are present between wild-type and VLW mice, a prominent increase in Argonaute-2-bound levels of microRNAs could be observed in VLW mice. This included microRNA-134, microRNA-99a and microRNA-101. Subsequent experiments revealed this increase in Argonaute-2 loading of microRNAs to correlate with increased microRNA expression. Our in vivo study suggests that a pathological tau overexpression may lead to an increase in active microRNAs, possibly contributing to dysregulation of gene expression and tau-induced pathology.