Abstract
Individual Alzheimer’s disease (AD) patients have been shown to have structurally distinct amyloid-β (Aβ) aggregates, including fibrils, in their brain. These findings suggest the possibility of a relationship between AD progression and Aβ fibril structures. Thus, the characterization of the structural dynamics of Aβ could aid the development of novel therapeutic strategies and diagnosis. Protein structure and dynamics have typically been studied separately. Most of the commonly used biophysical approaches are limited in providing substantial details regarding the combination of both structure and dynamics. On the other hand, high-speed atomic force microscopy (HS-AFM), which simultaneously visualizes an individual protein structure and its dynamics in liquid in real time, can uniquely link the structure and the kinetic details, and it can also unveil novel insights. Although amyloidogenic proteins generate heterogeneously aggregated species, including transient unstable states during the aggregation process, HS-AFM elucidated the structural dynamics of individual aggregates in real time in liquid without purification and isolation. Here, we review and discuss the HS-AFM imaging of amyloid aggregation and strategies to optimize the experiments showing findings from Aβ and amylin, which is associated with type II diabetes, shares some common biological features with Aβ, and is reported to be involved in AD.
Highlights
The relationship between neurodegenerative disease symptoms and the structural dynamics of associated amyloidogenic proteins has been revealed
We investigated how myricetin altered the structural dynamics of Aβ42 amyloid fibril formation using high-speed atomic force microscopy (HS-Atomic force microscopy (AFM))
The HS-AFM results suggested that the myricetin–monomer Aβ42 complex perturbed the dynamic equilibrium between the monomer and low molecular weight (LMW) that restricted the recruitment of LMW into the fibril ends
Summary
The relationship between neurodegenerative disease symptoms and the structural dynamics of associated amyloidogenic proteins has been revealed. The structural dynamics during the aggregation process depend on the surrounding physicochemical conditions in vivo, including the free-in-solution or membrane-bound forms, pH, and electrolytes. Aβ40, a 40 residue Aβ variant cleaved from the amyloid precursor protein (APP), is unstructured [14,15] and can form a lowly populated 310 helical structure in solution [16]; disordered oligomers were reported [17]. Tau [23], α-synuclein, and other amyloidogenic proteins, including amylin, formed ion-channel oligomers in the membrane [24]. Amyloid fibrils with different structures may reflect variable toxicity, aggregation pathways, and surrounding microenvironments in different patients and symptoms [1,42]. We show that HS-AFM links structural and dynamics studies, reviewing recent HS-AFM studies and including our findings for Aβ42 [93] and amylin [116], which is associated with type II diabetes and AD [117,118,119,120,121,122,123]
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