Visualization of soluble tau oligomers in the brain of TauP301L-BiFC transgenic mice reveals consequential events of tau aggregation

Abstract

Accumulation of abnormal tau aggregates in the brain is the pathological hallmark of multiple neurodegenerative disorders including Alzheimer’s disease. It is becoming apparent that soluble tau aggregates play a key role in tau pathology as a neurotoxic species causing neuronal cell death and also as a prion-like seed for mediating tau propagation. Despite the pathological importance, there is no single method that allows monitoring the formation of soluble tau aggregates in the brain. As a tool to investigate tau aggregation, we generated a novel tau transgenic mouse model that visualizes tau self-assembly in the brain. By introducing the bimolecular fluorescence complementation (BiFC) technique to tau, we were able to achieve a spatial and temporal resolution of tau aggregation in the brain of transgenic tau-BiFC mice. As an indication of tau aggregation, BiFC fluorescence was detected in diverse brain regions at 3 month and decreased at 6 months with the activation of proteolytic cleavage. The BiFC fluorescence increased significantly at 9 months as insoluble tau aggregates increased in the brain. Our tau-BiFC mice would be a useful tool for investigating tau pathology and evaluating tau-targeted therapeutics.