Structure-based inhibitors of amyloid beta core suggest a common interface with tau

eLife

Tamir Gonen¹  Justyna Sosna²  Stephan Philipp²  Charles G Glabe²  David S Eisenberg³  Paul Seidler⁴  Jose A Rodriguez⁴  Kevin A Murray⁴  Michael R Sawaya⁴  Sarah L Griner⁴  Tianxiao Peter Yang⁴  Shruti Sahay⁴  Jeannette Bowler⁴  Duilio Cascio⁴ 

[1] Biochemistry Department, Faculty of Science and Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia;Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, United States;Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, United States;UCLA-DOE Institute, Department of Biological Chemistry, Molecular Biology Institute, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States;

关键词: amyloid beta;    tau;    inhibitor;    MicroED;    amyloid;    cross-seeding;   

DOI  :  10.7554/eLife.46924

来源: DOAJ

【 摘 要 】

Alzheimer’s disease (AD) pathology is characterized by plaques of amyloid beta (Aβ) and neurofibrillary tangles of tau. Aβ aggregation is thought to occur at early stages of the disease, and ultimately gives way to the formation of tau tangles which track with cognitive decline in humans. Here, we report the crystal structure of an Aβ core segment determined by MicroED and in it, note characteristics of both fibrillar and oligomeric structure. Using this structure, we designed peptide-based inhibitors that reduce Aβ aggregation and toxicity of already-aggregated species. Unexpectedly, we also found that these inhibitors reduce the efficiency of Aβ-mediated tau aggregation, and moreover reduce aggregation and self-seeding of tau fibrils. The ability of these inhibitors to interfere with both Aβ and tau seeds suggests these fibrils share a common epitope, and supports the hypothesis that cross-seeding is one mechanism by which amyloid is linked to tau aggregation and could promote cognitive decline.

【 授权许可】

Unknown