Promotion and Inhibition of Amyloid-β Peptide Aggregation: Molecular Dynamics Studies

Itoh, Satoru; Okumura, Hisashi

doi:10.3390/ijms22041859

Cited by 15 publications

(31 citation statements)

References 106 publications

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“…The findings of our research on the binding interactions between compounds 1 – 4 and Aβ42 could be relevant in future research, such as the development of more effective Aβ42 aggregation inhibitors. These results agree well with previous published MD simulations of β-amyloid peptides [ 37 , 38 , 39 , 40 ], thereby offering promising leads towards development of potential therapeutics for AD.…”

Section: Resultssupporting

confidence: 92%

Combined Modeling Study of the Binding Characteristics of Natural Compounds, Derived from Psoralea Fruits, to β-Amyloid Peptide Monomer

Radwan

Alanazi

2022

IJMS

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A dysfunctional protein aggregation in the nervous system can lead to several neurodegenerative disorders that result in intracellular inclusions or extracellular aggregates. An early critical event within the pathogenesis of Alzheimer’s disease is the accumulation of amyloid beta peptide within the brain. Natural compounds isolated from Psoralea Fructus (PF) have significant anti-Alzheimer effects as strong inhibitors of Aβ42 aggregation. Computer simulations provide a powerful means of linking experimental findings to nanoscale molecular events. As part of this research four prenylated compounds, the active ingredients of Psoralea Fructus (PF), were studied as Aβ42 accumulation inhibitors using molecular simulations modeling. In order to resolve the binding modes of the ligands and identify the main interactions of Aβ42 residues, we performed a 100 ns molecular dynamics simulation and binding free energy calculations starting from the model of the compounds obtained from the docking study. This study was able to pinpoint the key amino acid residues in the Aβ42 active site and provide useful information that could benefit the development of new Aβ42 accumulation inhibitors.

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Section: Resultssupporting

confidence: 92%

Combined Modeling Study of the Binding Characteristics of Natural Compounds, Derived from Psoralea Fruits, to β-Amyloid Peptide Monomer

Radwan

Alanazi

2022

IJMS

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“…What makes these genes valuable for neurodegenerative and neuroprotective research is that they are mostly brain-specific genes that play critical roles in the maintenance of neuronal health. Amyloid Beta Precursor Protein, or simply APP, for example is a well-studied gene that is known to form the protein basis of the amyloid plaques found in the brains of patients with Alzheimer disease 42 . ATP1B1, on the other hand, encodes a key Na + /K + -ATPase that establishes and maintains the osmoregulation across the plasma membrane for proper neuronal excitability 43 .…”

Section: Discussionmentioning

confidence: 99%

Integrative genome-wide analysis of dopaminergic neuron-specific PARIS expression in Drosophila dissects recognition of multiple PPAR-γ associated gene regulation

Yazar

Kang

et al. 2021

Sci Rep

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The transcriptional repressor called parkin interacting substrate (PARIS; ZNF746) was initially identified as a novel co-substrate of parkin and PINK1 that leads to Parkinson’s disease (PD) by disrupting mitochondrial biogenesis through peroxisome proliferator-activated receptor gamma (PPARγ) coactivator -1α (PGC-1α) suppression. Since its initial discovery, growing evidence has linked PARIS to defective mitochondrial biogenesis observed in PD pathogenesis. Yet, dopaminergic (DA) neuron-specific mechanistic underpinnings and genome-wide PARIS binding landscape has not been explored. We employed conditional translating ribosome affinity purification (TRAP) followed by RNA sequencing (TRAP-seq) for transcriptome profiling of DA neurons in transgenic Drosophila lines expressing human PARIS wild type (WT) or mutant (C571A). We also generated genome-wide maps of PARIS occupancy using ChIP-seq in human SH-SY5Y cells. The results demonstrated that PPARγ functions as a master regulator of PARIS-induced molecular changes at the transcriptome level, confirming that PARIS acts primarily on PGC-1α to lead to neurodegeneration in PD. Moreover, we identified that PARIS actively modulates expression of PPARγ target genes by physically binding to the promoter regions. Together, our work revealed how PARIS drives adverse effects on modulation of PPAR-γ associated gene clusters in DA neurons.

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“…The atomiclevel structural changes during the Aβ aggregation process can be revealed by molecular dynamics (MD) simulations. Many MD simulations of Aβ and related peptides have been performed [15][16][17][18], such as the monomeric state [27,[34][35][36][37][38][39][40][41][42][43], dimerization [44][45][46][47][48][49][50][51][52][53][54][55][56][57], oligomerization [33,[58][59][60][61][62][63][64][65][66], amyloid-fibril elongation [67][68][69][70][71][72][73][74][75][76][77][78][79], amyloid-fibril stability …”

Section: Tachi Et Al: Aβ Peptides In Heterogeneous Environments E1900...mentioning

confidence: 99%

“…Aβ with 40 residues is known as Aβ40, and that with 42 residues is known as Aβ42. Aβ and its fragments have been the subject of many experimental and computational studies [5][6][7][8][9][10][11][12][13][14][15][16][17][18]. For example, solid-state nuclear magnetic resonance (NMR) experiments have revealed that two intermolecular β-sheet structures are formed in Aβ40 amyloid fibrils [8].…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamics simulations of amyloid-β peptides in heterogeneous environments

2022

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Edited by Akio Kitao Alzheimer's disease is thought to be caused by the aggregation of amyloid-β (Aβ) peptides. Their aggregation is accelerated at hydrophilic/hydrophobic interfaces such as the air-water interface and the surface of monosialotetrahexosylganglioside (GM1) clusters on neuronal cell membranes. In this review, we present recent studies of full-length Aβ (Aβ40) peptides and Aβ(16-22) fragments in such heterogeneous environments by molecular dynamics (MD) simulations. These peptides have both hydrophilic and hydrophobic amino-acid residues and tend to exist at the hydrophilic/hydrophobic interface. Therefore, the peptide concentration increases at the interface, which is one of the factors that promote aggregation. Furthermore, it was found that Aβ40 forms an α-helix structure and then a β-hairpin structure at the interface. The β-hairpin promotes the formation of oligomers with intermolecular β-sheets. It means that not only the high concentration of Aβ40 at the interface but also the structure of Aβ40 itself promotes aggregation. In addition, MD simulations of Aβ40 on recently-developed GM1-glycan clusters showed that the HHQ (13-15) segment of Aβ40 is important for the recognition of GM1glycan clusters. It was also elucidated that Aβ40 forms a helix structure in the C-terminal region on the GM1glycan cluster. This result suggests that the helix formation, which is the first step in the conformational changes toward pathological aggregation, is initiated at the GM1-glycan moieties rather than at the lipid-ceramide moieties. These studies will enhance the physicochemical understanding of the structural changes of Aβ at the heterogeneous interfaces and the mechanism of Alzheimer's disease pathogenesis.

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Promotion and Inhibition of Amyloid-β Peptide Aggregation: Molecular Dynamics Studies

Cited by 15 publications

References 106 publications

Combined Modeling Study of the Binding Characteristics of Natural Compounds, Derived from Psoralea Fruits, to β-Amyloid Peptide Monomer

Combined Modeling Study of the Binding Characteristics of Natural Compounds, Derived from Psoralea Fruits, to β-Amyloid Peptide Monomer

Integrative genome-wide analysis of dopaminergic neuron-specific PARIS expression in Drosophila dissects recognition of multiple PPAR-γ associated gene regulation

Molecular dynamics simulations of amyloid-β peptides in heterogeneous environments

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