National Institutes of Health/National Institute on Aging (NIH/NIA)
1R01 AG029430
米国
National Institutes of Health/National Institute on Aging (NIH/NIA)
RF1 AG054022
米国
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
1F32 NS095661
米国
BrightFocus Foundation
A2016588F
米国
引用
ジャーナル: Nat Chem / 年: 2018 タイトル: Structure-based inhibitors of tau aggregation. 著者: P M Seidler / D R Boyer / J A Rodriguez / M R Sawaya / D Cascio / K Murray / T Gonen / D S Eisenberg / 要旨: Aggregated tau protein is associated with over 20 neurological disorders, which include Alzheimer's disease. Previous work has shown that tau's sequence segments VQIINK and VQIVYK drive its ...Aggregated tau protein is associated with over 20 neurological disorders, which include Alzheimer's disease. Previous work has shown that tau's sequence segments VQIINK and VQIVYK drive its aggregation, but inhibitors based on the structure of the VQIVYK segment only partially inhibit full-length tau aggregation and are ineffective at inhibiting seeding by full-length fibrils. Here we show that the VQIINK segment is the more powerful driver of tau aggregation. Two structures of this segment determined by the cryo-electron microscopy method micro-electron diffraction explain its dominant influence on tau aggregation. Of practical significance, the structures lead to the design of inhibitors that not only inhibit tau aggregation but also inhibit the ability of exogenous full-length tau fibrils to seed intracellular tau in HEK293 biosensor cells into amyloid. We also raise the possibility that the two VQIINK structures represent amyloid polymorphs of tau that may account for a subset of prion-like strains of tau.