Tauopathy strain properties are independent of tau isoform compositions

Identification: He, Zhuohao


Tauopathy strain properties are independent of tau isoform compositions
Zhuohao He1, Jing L. Guo1, Jennifer D. McBride1, Soojung Kim1, Hyesung Kim1, Sneha Narasimhan1, Lakshmi Changolkar1, Bin Zhang1, Ronald J. Gathagan1, Hannah Brown1, Gerald D. Schellenberg1, John Q. Trojanowski1, Virginia M.-Y. Lee1,3,*
1Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
*Corresponding author: Virginia M.-Y. Lee - vmylee@upenn.edu
Pathological tau deposit is a common feature in several neurodegenerative diseases, called tauopathies, including Alzheimer's disease (AD), Corticobasal degeneration (CBD), Progressive spranuclear palsy (PSP) and Pick's disease (PiD). Although 6 isoform tau with equal amount 3R and 4R microtubule binding repeats are expressed in adult human brain, the pathological tau in different tauopathy brains exhibit distinct isoform compositions and cell type localizations, which are considered as strain properties. The mechanisms underlying the pathogenesis of such distinct tau strains are unknown. It is not clear whether distinct isoform compositions determine different strain properties or vice versa. To address this question, we generated a novel biogenic mouse line 6hTau that only express human 6 isoform tau, with an equal ratio of 3R and 4R repeats. Through intracerebral inoculation of distinct human tauopathy brain-derived tau strains as we did recently1,2, we developed a group of tauopathy mouse models that could respectively recapitulate the tau pathogenesis in distinct tauopathy diseases, in terms of isoform composition and cell type localization. Moreover, through in vivo propagating different tau strains among the mouse lines respectively expressing only 3R, or 4R or both isoform tau, we provide evidences suggesting distinct tau strain properties are independent of their isoform composition, but more likely rely on their distinct pathological protein conformations. Our study developed the most-pathological relevant tauopathy mouse models to date, and provides novel insights on the mechanisms underlying distinct tauopathy pathogenesis.  
  1. He Z. et al., Nat Med. 24(1), 29-38, doi: 10.1038/nm.4443 (2018)
  2. Narasimhan S., et al., J Neurosci. 37(47), 11406-11423, doi: 10.1523/JNEUROSCI.1230-17.2017



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