Abstract
Significant research on Alzheimer’s disease (AD) has demonstrated that amyloid β (Aβ) oligomers are toxic molecules against neural cells. Thus, determining the generation mechanism of toxic Aβ oligomers is crucial for understanding AD pathogenesis. Aβ fibrils were reported to be disaggregated by treatment with small compounds, such as epigallocatechin gallate (EGCG) and dopamine (DA), and a loss of fibril shape and decrease in cytotoxicity were observed. However, the characteristics of intermediate products during the fibril disaggregation process are poorly understood. In this study, we found that cytotoxic Aβ aggregates are generated during a moderate disaggregation process of Aβ fibrils. A cytotoxicity assay revealed that Aβ fibrils incubated with a low concentration of EGCG and DA showed higher cytotoxicity than Aβ fibrils alone. Atomic force microscopy imaging and circular dichroism spectrometry showed that short and narrow protofilaments, which were highly stable in the β-sheet structure, were abundant in these moderately disaggregated samples. These results indicate that toxic Aβ protofilaments are generated during disaggregation from amyloid fibrils, suggesting that disaggregation of Aβ fibrils by small compounds may be one of the possible mechanisms for the generation of toxic Aβ aggregates in the brain.
Highlights
Alzheimer’s disease (AD) is a major cause of dementia, and many researchers are attempting to develop diagnostic methods and drastic treatments
Different concentrations (50, 450, and 900 μM) of epigallocatechin gallate (EGCG) were added to 90 μM of amyloid β (Aβ) fibrils, and the mixture was incubated for several periods to determine the preparation conditions to obtain Aβ samples rich in toxic Aβ oligomers
Under the EGCG mixing conditions, the Thioflavin T (ThT) fluorescence intensity decreased in a compound concentration- and time-dependent manner compared to the Aβ fibrils alone (Figure 1A)
Summary
Alzheimer’s disease (AD) is a major cause of dementia, and many researchers are attempting to develop diagnostic methods and drastic treatments. To understand the buildup of Aβ oligomers, the aggregation process of Aβ has mostly been investigated In this process, intrinsically disordered Aβ monomers spontaneously aggregate to form mature insoluble amyloid fibrils, and various types of Aβ oligomers are generated as intermediate products [6]. Small and globular oligomers grow into protofilaments, in which several Aβ monomers are stacked to form a typical cross-β-sheet structure. Considering the disaggregation process, toxic HMW Aβ aggregates, such as protofilaments and protofibrils, are highly likely to be generated in the initial phase of fibril disaggregation, which is a disassembly of mature amyloid fibrils consisting of Aβ. A cell viability assay, AFM imaging, and circular dichroism (CD) spectrometry measurements were performed to determine the cytotoxicity and structure of moderately disaggregated Aβ aggregates. We tested dopamine (DA), a neurotransmitter found in the brain, as a small compound that disassembles amyloid fibril structures
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