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

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.

Dynamics and Structures of Amyloid Aggregates under Fluid Flows

“…We also show that fluid flow acts as a mechanical perturbation that can drastically modify the shape of aggregates, depending on their geometry and size. Notably, we show that fibrils, because of their elasticity, acquire loop conformations, as recently experimentally reported at a different length scale . Our results are also relevant for the application of microfluidic devices to study the aggregation of complex biomolecular structures.…”

“…Finally, for even higher shear rate, the fibril folds in a stable annular shape, a pathogenic conformation that has been found at different scales in brain tissues and is highly toxic. 50 Interestingly, the annular fibrils, albeit different in structure, are also comparable in size to previously reported Aβ ion channels formed by assembled small subunits. 51 Large aggregates in Poiseuille f low.…”

“…Notably, we show that fibrils, because of their elasticity, acquire loop conformations, as recently experimentally reported at a different length scale. 50 Our results are also relevant for the application of microfluidic devices to study the aggregation of complex biomolecular structures.…”

Alzheimer’s Disease: A Molecular Model and Implied Path to Improved Therapy

“…(1) A virus assembly-associated version of the viral capsid (not the virus) is the AD trigger. (2) The triggering of symptoms is protein conformation-based, specifically, α-sheet-based. In our opinion, the integration of data of various types is the key step needed to form a more complete understanding of the disease and possible therapies.…”

“…Several neurodegenerative diseases, including Alzheimer’s disease (AD), are usually associated with excess in-brain production of extracellular, β-sheet-structured proteins, usually thought to be causative. This protein is generically called amyloid because of its starch-like texture (recently reviewed [ 1 , 2 , 3 , 4 , 5 ]). Therapies for AD are usually designed to promote the removal or destruction of amyloid proteins (Aβ protein in the case of AD) or their cleavage products, based on the hypothesis that the observed amyloid causes disease (amyloid cascade hypothesis [ 6 , 7 , 8 ]).…”