Visualization of soluble tau oligomers in TauP301L-BiFC transgenic mice demonstrates the progression of tauopathy. (April 2020)

• Record Type: Journal Article
• Authors: Shin, Seulgi; Kim, Dohee; Song, Ji Yeon; Jeong, Hyeanjeong; Hyeon, Seung Jae; Kowall, Neil W.; Ryu, Hoon; Pae, Ae Nim; Lim, Sungsu; Kim, Yun Kyung
• Is Part Of: Progress in neurobiology. Volume 187(2020)
• Publication Date: 2020-04
• Subjects: Tau -- P301L -- BiFC -- Tau transgenic mouse -- Tau oligomer -- Tauopathy; Neurobiology -- Periodicals; Neurology -- Periodicals; Neurology -- Periodicals; Neurobiologie -- Périodiques; 612.8
• DOI: 10.1016/j.pneurobio.2020.101782
• Languages: English
• ISSNs: 0301-0082

Abstract

Highlights: Tau oligomer plays a critical role in tau pathology. Tau oligomers become an important therapeutic target for tauopathies. For now, there is no evaluation method for tau oligomerization in vivo . By introducing BiFC techniques to tau, tau-BiFC mouse model provides spatial and temporal resolution of tau oligomerization in the brain Abstract: Accumulation of abnormal tau aggregates in the brain is a pathological hallmark of multiple neurodegenerative disorders including Alzheimer's disease. Increasing evidence suggests that soluble tau aggregates play a key role in tau pathology as neurotoxic species causing neuronal cell death and act as prion-like seeds mediating tau propagation. Despite the pathological relevance, there is a paucity of methods to monitor tau oligomerization in the brain. As a tool to monitor tau self-assembly in the brain, we generated a novel tau transgenic mouse, named TauP301L-BiFC. By introducing bimolecular fluorescence complementation technique to human tau containing a P301L mutation, we were able to monitor and quantify tau self-assembly, represented by BiFC fluorescence in the brains of transgenic TauP301L-BiFC mice. TauP301L-BiFC mice showed soluble tau oligomerization from 3 months, showing significantly enriched BiFC fluorescence in the brain. Then, massive tau fragmentation occured at 6 months showing dramatically decreased TauP301L-BiFC fluorescence. The fragmented tau species served as a seed for insoluble tau aggregation. In a result, insoluble TauP301L-BiFC aggregates coaggregated with endogenous mouse tau accumulated in the brain, showing subsequently increased BiFC fluorescence from 9 months. Neuronal degeneration and cognitive deficits were observed from 12 months of age. TauP301L-BiFC mouse model demonstrated that methylene blue reduced the amount of soluble tau oligomers in the brain, resulting in the prevention of cognitive impairments. We assure that TauP301L-BiFC mice are a bona-fide animal tool to monitor pathological tau oligomerization in AD and other tauopathies.