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한국과학기술연구원(KIST), UST

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Prog. Neurobiol., Available online 24 February 2020, 101782 | https://doi.org/10.1016/j.pneurobio.2020.101782 Visualization of soluble tau oligomers in TauP301L-BiFC transgenic mice demonstrates the progression of tauopathy

Seulgi Shin^a,e, Dohee Kim^a,c, Ji Yeon Song^a,c, Hyeanjeong Jeong^a,b,c, Seung Jae Hyeon^c, Neil W. Kowall^c,d, Hoon Ryu^c,d, Ae Nim Pae^a,e, Sungsu Lim^a,c,*, Yun Kyung Kim^a,c,e,*

^aConvergence Research Center for Diagnosis, Treatment and Care System of Dementia, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea
^b Department of Life Sciences, School of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
^cCenter for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea
^dBoston University Alzheimer’s Disease Center and Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA
^eDivision of Bio-Medical Science & Technology, KIST School, University of Science and Technology (UST), Seoul, 02792, Republic of Korea

^*Corresponding authors : Sungsu Lim, Yun Kyung Kim

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 inroducing 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.

Keywords : Tau; P301L; BiFC; Tau transgenic mouse; Tau oligomer; Tauopathy

논문정보

형식Research article
게재일2020년 02월 (BRIC 등록일 2020-03-11)
연구진국내(교신)+국외 연구진
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