Feasibility of β-Sheet Breaker Peptide-H102 Treatment for Alzheimer's Disease Based on β-Amyloid Hypothesis

Lin, Li‐Rong; BO, Xiangyu; Tan, Yuanzhen; Sun, Feng-Xian; Song, Ming; Zhao, Junxing; Ma, Zhigui; Li, Mei; ZHENG, Kaijun; Xu, Sihua

doi:10.1371/journal.pone.0112052

Cited by 28 publications

(16 citation statements)

References 43 publications

(52 reference statements)

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“…According to the domain swapping hypothesis a multimolecular aggregate emerges as a result of uncoiling of a domain fragment, leaving behind a pocket which accommodates the uncoiled fragment of another molecule [11]. Improperly folded proteins (or individual domains) lead to pathological changes commonly referred to as misfolding diseases [12]. …”

Section: Introductionmentioning

confidence: 99%

Structural Interface Forms and Their Involvement in Stabilization of Multidomain Proteins or Protein Complexes

Dygut

Kalinowska

Banach

et al. 2016

IJMS

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The presented analysis concerns the inter-domain and inter-protein interface in protein complexes. We propose extending the traditional understanding of the protein domain as a function of local compactness with an additional criterion which refers to the presence of a well-defined hydrophobic core. Interface areas in selected homodimers vary with respect to their contribution to share as well as individual (domain-specific) hydrophobic cores. The basic definition of a protein domain, i.e., a structural unit characterized by tighter packing than its immediate environment, is extended in order to acknowledge the role of a structured hydrophobic core, which includes the interface area. The hydrophobic properties of interfaces vary depending on the status of interacting domains—In this context we can distinguish: (1) Shared hydrophobic cores (spanning the whole dimer); (2) Individual hydrophobic cores present in each monomer irrespective of whether the dimer contains a shared core. Analysis of interfaces in dystrophin and utrophin indicates the presence of an additional quasi-domain with a prominent hydrophobic core, consisting of fragments contributed by both monomers. In addition, we have also attempted to determine the relationship between the type of interface (as categorized above) and the biological function of each complex. This analysis is entirely based on the fuzzy oil drop model.

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Section: Introductionmentioning

confidence: 99%

Structural Interface Forms and Their Involvement in Stabilization of Multidomain Proteins or Protein Complexes

Dygut

Kalinowska

Banach

et al. 2016

IJMS

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“…Previously, we designed a β-sheet breaker peptide, H102, that could inhibit Aβ aggregation as well as reducing amyloid load in the brains of APP/PS1 transgenic mice, thus limiting brain damage and improving the symptoms of AD in animal models (He et al, 2008 ; Lin et al, 2014 ). However, H102 was not stable in vitro .…”

Section: Discussionmentioning

confidence: 99%

“…The behavioral test was performed after 30 days of intranasal administration using the Morris Water Maze (MWM) according to our previous report (Lin et al, 2014 ). Briefly, the MWM test was conducted in a circular pool with a diameter of 80 and 32 cm deep.…”

Section: Methodsmentioning

confidence: 99%

“…β-sheet breaker peptides are homologous to regions of the β-sheet hydrophobic carboxyl segments and highly effective in inhibiting Aβ amyloidogenesis (Jarrett et al, 1993 ). Based on the amino acid residues 17–21 of Aβ 1−42 , we previously designed a β-sheet breaker peptide H102 (His-Lys-Gln-Leu-Pro-Phe-Phe-Glu-Glu-Asp) that can reduce amyloid load and cerebral damage and improve the learning and memory ability of AD animal models (He et al, 2008 ; Lin et al, 2014 ). However, H102 was not very stable.…”

Section: Introductionmentioning

confidence: 99%

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β-Sheet Breaker Peptide-HPYD for the Treatment of Alzheimer's Disease: Primary Studies on Behavioral Test and Transcriptional Profiling

et al. 2018

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Background: Alzheimer's disease (AD), is a progressive neurodegenerative disease that is characterized by cognitive loss. Most researchers believe that aggregation and accumulation of β-amyloid peptides (Aβ) in brain cells are the central pathological hallmark of this disease.Methods: Based on the amyloid hypothesis, a 10 amino acids β-sheet breaker peptide HPYD (His-Lys-Gln-Leu-Pro-Phe-Tyr-Glu-Glu-Asp) was designed according to the structure and sequence of the previous designed peptide H102. Accelerated stability test, thioflavine T (ThT) fluorescence spectral analysis and transmission electron microscopy (TEM) imaging were performed to detect the stability and inhibitory effects on the aggregation of Aβ1−42 by H102 and HPYD. FITC-labeled HPYD was first tested to determine whether it could be transferred along the olfactory pathway to the brain after nasal administration to mice. Subsequently, the Morris Water Maze (MWM) test for behavioral analysis was used to investigate the learning and memory ability of APP/PS1 transgenic mice by HPYD. Immunohistochemistry and western blot analysis was performed to determine the role of HPYD on Aβ and APP protein levels. In addition, microarray analysis was used to evaluate the effect of HPYD on gene expression in AD mouse models.Results: Our in vitro results demonstrated that HPYD had enhanced stability and inhibitory effects on Aβ1−42 aggregation compared to H102. HPYD could be delivered into the brain through nasal administration and improved the learning and memory ability in APP/PS1 transgenic mouse models by reducing Aβ and APP protein levels. In addition, microarray analyses suggested that several genes related to the inflammatory pathway, AD and gluco-lipid metabolism were dysregulated and could be restored to almost normal levels after HPYD administration to mice.Conclusions: Our results demonstrated that HPYD could be a potential therapeutic drug candidate for the treatment of AD.

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“…It has been proved that Aβ16-20 (KLVFF) could bind to its homologous sequence in Aβ, serving as an inhibitor to Aβ aggregation [14]. Based on this fragment, various modifications such as amino acid addition [15][16][17][18] or replacement (V18P) [19][20][21][22], N-methylation [23][24][25], cyclization [26,27], branching [28,29] and functionalizing the N-or C-terminal with various organic moieties [30][31][32] have been studied to improve the inhibition effect. Moreover, FF motif has served as a key platform for the design of peptide and peptidomimetic inhibitors of Aβ fibrillation [33].…”

Section: Introductionmentioning

confidence: 99%

Aromatic-interaction-mediated inhibition of β-amyloid assembly structures and cytotoxicity

et al. 2017

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Abnormal aggregation of β-amyloid (Aβ) peptide plays an important role in the onset and progress of Alzheimer's disease (AD); hence, targeting Aβ aggregation is considered as an effective therapeutic strategy. Here, we studied the aromatic-interaction-mediated inhibitory effect of oligomeric polypeptides (K8Y8, K4Y8, K8W8) on Aβ42 fibrillization process. The polypeptides containing lysine as well as representative aromatic amino acids of tryptophan or tyrosine were found to greatly suppress the aggregation as evaluated by thioflavin T assay. Circular dichroism spectra showed that the β-sheet formation of Aβ42 peptides decreased with the polypeptide additives. Molecular docking studies revealed that the oligomeric polypeptides could preferentially bind to Aβ42 through π-π stacking between aromatic amino acids and Phe19, together with hydrogen bonding. The cell viability assay confirmed that the toxicity of Aβ42 to SH-SY5Y cells was markedly reduced in the presence of polypeptides. This study could be beneficial for developing peptide-based inhibitory agents for amyloidoses. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

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Feasibility of β-Sheet Breaker Peptide-H102 Treatment for Alzheimer's Disease Based on β-Amyloid Hypothesis

Cited by 28 publications

References 43 publications

Structural Interface Forms and Their Involvement in Stabilization of Multidomain Proteins or Protein Complexes

Structural Interface Forms and Their Involvement in Stabilization of Multidomain Proteins or Protein Complexes

β-Sheet Breaker Peptide-HPYD for the Treatment of Alzheimer's Disease: Primary Studies on Behavioral Test and Transcriptional Profiling

Aromatic-interaction-mediated inhibition of β-amyloid assembly structures and cytotoxicity

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