Repository logo
 

Formation of amyloid loops in brain tissues is controlled by the flexibility of protofibril chains.

Published version
Peer-reviewed

Repository DOI


Type

Article

Change log

Authors

Abstract

Neurodegenerative diseases, such as Alzheimer's disease (AD), are associated with protein misfolding and aggregation into amyloid fibrils. Increasing evidence suggests that soluble, low-molecular-weight aggregates play a key role in disease-associated toxicity. Within this population of aggregates, closed-loop pore-like structures have been observed for a variety of amyloid systems, and their presence in brain tissues is associated with high levels of neuropathology. However, their mechanism of formation and relationship with mature fibrils have largely remained challenging to elucidate. Here, we use atomic force microscopy and statistical theory of biopolymers to characterize amyloid ring structures derived from the brains of AD patients. We analyze the bending fluctuations of protofibrils and show that the process of loop formation is governed by the mechanical properties of their chains. We conclude that ex vivo protofibril chains possess greater flexibility than that imparted by hydrogen-bonded networks characteristic of mature amyloid fibrils, such that they are able to form end-to-end connections. These results explain the diversity in the structures formed from protein aggregation and shed light on the links between early forms of flexible ring-forming aggregates and their role in disease.

Description

Keywords

amyloid pore, atomic force microscopy, protein aggregation, Humans, Amyloid, Amyloid beta-Peptides, Alzheimer Disease, Amyloidogenic Proteins, Brain, Microscopy, Atomic Force

Journal Title

Proc Natl Acad Sci U S A

Conference Name

Journal ISSN

0027-8424
1091-6490

Volume Title

120

Publisher

Proceedings of the National Academy of Sciences