Subtle change of fibrillation condition leads to substantial alteration of recombinant Tau fibril structure

Xiang Li; Shenqing Zhang; Zhengtao Liu; Youqi Tao; Wencheng Xia; Yunpeng Sun; Cong Liu; Weidong Le; Bo Sun; Dan Li

doi:10.1016/j.isci.2022.105645

Subtle change of fibrillation condition leads to substantial alteration of recombinant Tau fibril structure

iScience. 2022 Nov 22;25(12):105645. doi: 10.1016/j.isci.2022.105645. eCollection 2022 Dec 22.

Authors

Xiang Li¹, Shenqing Zhang¹, Zhengtao Liu^{2

3}, Youqi Tao¹, Wencheng Xia^{2

3}, Yunpeng Sun^{2

3}, Cong Liu^{2

4}, Weidong Le⁵, Bo Sun⁶, Dan Li^{1

7

8}

Affiliations

¹ Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China.
² Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China.
³ University of the Chinese Academy of Sciences, Beijing 100049, China.
⁴ State Key Laboratory of Bio-Organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
⁵ Institute of Neurology, Sichuan Academy of Medical Sciences-Sichuan Provincial Hospital, Chengdu 610072, China.
⁶ School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
⁷ Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai 200240, China.
⁸ WLA Laboratories, World Laureates Association, Shanghai 201203, China.

Abstract

In vitro assembly of amyloid fibrils that recapitulate those in human brains is very useful for fundamental and applied research on the amyloid formation, pathology, and clinical detection. Recent success in the assembly of Tau fibrils in vitro enables the recapitulation of the paired helical filament (PHF) of Tau extracted from brains of patients with Alzheimer's disease (AD). However, following the protocol, we observed that Tau constructs including 297-391 and a mixture of 266-391 (3R)/297-391, which are expected to predominantly form PHF-like fibrils, form highly heterogeneous fibrils instead. Moreover, the seemingly PHF-like fibril formed by Tau 297-391 exhibits a distinctive atomic structure with a spindle-like fold, that is neither PHF-like or similar to any known Tau fibril structures revealed by cryo-electron microscopy (cryo-EM). Our work highlights the high sensitivity of amyloid fibril formation to subtle conditional changes and suggests high-resolution structural characterization to in vitro assembled fibrils prior to further laboratory use.

Keywords: Neuroscience; cell biology; structural biology.