Abstract
Both amyloid-β (Aβ) and insulin are amyloidogenic peptides, and they play a critical role in Alzheimer’s disease (AD) and type-2 diabetes (T2D). Misfolded or aggregated Aβ and glycated insulin are commonly found in AD and T2D patients, respectively, and exhibit neurotoxicity and oxidative stress. The present study examined the anti-Aβ25-35 aggregation and anti-insulin glycation activities of five phlorotannins isolated from Ecklonia stolonifera. Thioflavin-T assay results suggest that eckol, dioxinodehydroeckol, dieckol, and phlorofucofuroeckol-A (PFFA) significantly inhibit Aβ25-35 self-assembly. Molecular docking and dynamic simulation analyses confirmed that these phlorotannins have a strong potential to interact with Aβ25-35 peptides and interrupt their self-assembly and conformational transformation, thereby inhibiting Aβ25-35 aggregation. In addition, PFFA dose-dependently inhibited d-ribose and d-glucose induced non-enzymatic insulin glycation. To understand the molecular mechanism for insulin glycation and its inhibition, we predicted the binding site of PFFA in insulin via computational analysis. Interestingly, PFFA strongly interacted with the Phe1 in insulin chain-B, and this interaction could block d-glucose access to the glycation site of insulin. Taken together, our novel findings suggest that phlorofucofuroeckol-A could be a new scaffold for AD treatment by inhibiting the formation of β-sheet rich structures in Aβ25-35 and advanced glycation end-products (AGEs) in insulin.
Highlights
The aberrant aggregation of misfolded proteins within a biological system is responsible for various pathological conditions
We screened the inhibitory effects of five phlorotannins on Amyloid β-protein fragment 25–35 (Aβ25-35) self-aggregation at a concentration of 10 μM using thioflavin-T fluorescence
The many neuroprotective effects of various phlorotannins are being reported, including inhibitory activity against enzymes linked to the pathogenesis of Alzheimer’s disease (AD) and Parkinson’s disease (PD) [22,24,25,32], modulatory activity against G-protein coupled receptors related to neuronal diseases such as PD and psychological diseases [22,23], and free-radical scavenging activity [15]
Summary
The aberrant aggregation of misfolded proteins within a biological system is responsible for various pathological conditions. Protein aggregates commonly form and accumulate during normal aging, and it remains unclear whether misfolded proteins are a cause or consequence of aging [1]. Protein aggregates are the major hallmarks of numerous neurodegenerative and metabolic disorders, and many central nervous system pathologies are associated with protein aggregation, such as amyloid-β peptide (Aβ) and tau protein aggregates in Alzheimer’s disease (AD), α-synuclein in Parkinson’s disease (PD), and the huntingtin protein in Huntington’s disease [2]. The Aβ peptide is a byproduct of proteolytic processing of the amyloid precursor protein, a transmembrane protein, by β- and γ-secretases. The initial cleavage of Aβ forms soluble and non-toxic monomers of varying lengths, the most common of which are the Aβ1–40 and Aβ1–42 peptides.
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