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1.
Severe early-onset familial Alzheimer''s disease (FAD) is caused by more than 200 different mutations in the genes coding for presenilin, the catalytic subunit of the 4-subunit protease complex γ-secretase, which cleaves the C99 fragment of the amyloid precursor protein (APP) to produce Aβ peptides. γ-Secretase exists with either of two homologues, PS1 and PS2. All cryo-electron microscopic structures and computational work has so far focused on γ-secretase with PS1, yet PS2 mutations also cause FAD. A central question is thus whether there are structural and dynamic differences between PS1 and PS2. To address this question, we use the cryo-electron microscopic data for PS1 to develop the first structural and dynamic model of PS2-γ-secretase in the catalytically relevant mature membrane-bound state at ambient temperature, equilibrated by three independent 500 ns molecular dynamics simulations. We find that the characteristic nicastrin extra-cellular domain breathing mode and major movements in the cytosolic loop between TM6 and TM7 occur in both PS2- and PS1-γ-secretase. The overall structures and conformational states are similar, suggesting similar catalytic activities. However, at the sequence level, charge-controlled membrane-anchoring is extracellular for PS1 and intracellular for PS2, which suggests different subcellular locations. The tilt angles of the TM2, TM6, TM7 and TM9 helices differ in the two forms of γ-secretase, suggesting that the two proteins have somewhat different substrate processing and channel sizes. Our MD simulations consistently indicated that PS2 retains several water molecules near the catalytic site at the bilayer, as required for catalysis. The possible reasons for the differences of PS1 and PS2 are discussed in relation to their location and function.We constructed a model of presenilin-2 γ-secretase in the membrane and studied it by all-atom molecular dynamics simulations. The study provides the first structural-dynamic comparison of presenilin 1 and 2 relevant to Alzheimer''s disease. 相似文献
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Gender- and Age-Dependent γ-Secretase Activity in Mouse Brain and Its Implication in Sporadic Alzheimer Disease
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Alzheimer disease (AD) is an age-related disorder. Aging and female gender are two important risk factors associated with sporadic AD. However, the mechanism by which aging and gender contribute to the pathogenesis of sporadic AD is unclear. It is well known that genetic mutations in γ-secretase result in rare forms of early onset AD due to the aberrant production of Aβ42 peptides, which are the major constituents of senile plaques. However, the effect of age and gender on γ-secretase has not been fully investigated. Here, using normal wild-type mice, we show mouse brain γ-secretase exhibits gender- and age-dependent activity. Both male and female mice exhibit increased Aβ42Aβ40 ratios in aged brain, which mimics the effect of familial mutations of Presenilin-1, Presenlin-2, and the amyloid precursor protein on Aβ production. Additionally, female mice exhibit much higher γ-secretase activity in aged brain compared to male mice. Furthermore, both male and female mice exhibit a steady decline in Notch1 γ-secretase activity with aging. Using a small molecule affinity probe we demonstrate that male mice have less active γ-secretase complexes than female mice, which may account for the gender-associated differences in activity in aged brain. These findings demonstrate that aging can affect γ-secretase activity and specificity, suggesting a role for γ-secretase in sporadic AD. Furthermore, the increased APP γ-secretase activity seen in aged females may contribute to the increased incidence of sporadic AD in women and the aggressive Aβ plaque pathology seen in female mouse models of AD. In addition, deceased Notch γ-secretase activity may also contribute to neurodegeneration. Therefore, this study implicates altered γ-secretase activity and specificity as a possible mechanism of sporadic AD during aging. 相似文献
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Maria Szaruga Sarah Veugelen Manasi Benurwar Sam Lismont Diego Sepulveda-Falla Alberto Lleo Natalie S. Ryan Tammaryn Lashley Nick C. Fox Shigeo Murayama Harrie Gijsen Bart De Strooper Lucía Chávez-Gutiérrez 《The Journal of experimental medicine》2015,212(12):2003-2013
Presenilin (PSEN) pathogenic mutations cause familial Alzheimer’s disease (AD [FAD]) in an autosomal-dominant manner. The extent to which the healthy and diseased alleles influence each other to cause neurodegeneration remains unclear. In this study, we assessed γ-secretase activity in brain samples from 15 nondemented subjects, 22 FAD patients harboring nine different mutations in PSEN1, and 11 sporadic AD (SAD) patients. FAD and control brain samples had similar overall γ-secretase activity levels, and therefore, loss of overall (endopeptidase) γ-secretase function cannot be an essential part of the pathogenic mechanism. In contrast, impaired carboxypeptidase-like activity (γ-secretase dysfunction) is a constant feature in all FAD brains. Significantly, we demonstrate that pharmacological activation of the carboxypeptidase-like γ-secretase activity with γ-secretase modulators alleviates the mutant PSEN pathogenic effects. Most SAD cases display normal endo- and carboxypeptidase-like γ-secretase activities. However and interestingly, a few SAD patient samples display γ-secretase dysfunction, suggesting that γ-secretase may play a role in some SAD cases. In conclusion, our study highlights qualitative shifts in amyloid-β (Aβ) profiles as the common denominator in FAD and supports a model in which the healthy allele contributes with normal Aβ products and the diseased allele generates longer aggregation-prone peptides that act as seeds inducing toxic amyloid conformations.Early-onset familial Alzheimer’s disease (AD [FAD]), starting before age 65, is mainly caused by mutations in the Presenilin 1/2 (PSEN1/2) or the amyloid precursor protein (APP) genes and represents less than 0.1% of the total AD cases (Campion et al., 1999). Although rare, FAD offers a unique model to gain insights into the molecular mechanisms and etiology of sporadic AD (SAD).PSEN is the catalytic subunit of the γ-secretase complex (De Strooper et al., 1998; Wolfe et al., 1999), an intramembrane multimeric protease involved in the processing of many type 1 transmembrane proteins; among them, the Notch receptors and APP have received much attention because of their association with crucial cell signaling events or with AD pathogenesis, respectively (for a review see Jurisch-Yaksi et al. [2013]). Nicastrin (Nct), PSEN enhancer 2 (Pen2), and anterior pharynx defective 1 (APH1) are, together with PSEN, essential components of the protease complex (De Strooper, 2003).More than 150 pathogenic mutations in PSEN1 have been reported so far (http://www.molgen.ua.ac.be/ADMutations); and notably, the vast majority are missense substitutions distributed throughout the primary structure of PSEN1. PSEN/γ-secretase hydrolyzes peptide bonds in a process called regulated intramembrane proteolysis, which allows translation of extracellular signals into the cell. Compelling evidence indicates that γ-secretase cuts membrane proteins sequentially: the first endopeptidase cleavage (ε) releases a soluble intracellular domain (ICD), which may translocate to the nucleus to regulate gene expression while the remaining N-terminal transmembrane domain (TMD) fragment is successively cut by the carboxypeptidase-like activity of γ-secretase (γ-cleavages). Endopeptidase products, either amyloid-β49 (Aβ49) or Aβ48, are then processed along two major product lines: Aβ49 → Aβ46 → Aβ43 → Aβ40 or Aβ48 → Aβ45 → Aβ42 → Aβ38 (Takami et al., 2009). Every γ-cleavage removes a short C-terminal peptide from the TMD, reducing its hydrophobicity and increasing the probability of release. Secretion of an N-terminal fragment into the extracellular/luminal space terminates this sequence (Qi-Takahara et al., 2005; Yagishita et al., 2008; Takami et al., 2009). Importantly, the efficiency of the endopeptidase cleavage determines ICD product levels, which acquires high physiological relevance in the case of the Notch substrate. The carboxypeptidase-like efficiency, the number of cuts per substrate, determines the length of the N-terminal products; the level of efficiency is pathologically very relevant in the case of the APP substrate, as lower efficiency results in the production of longer and more aggregation-prone Aβ peptides (Chávez-Gutiérrez et al., 2012).How mutations in the PSENs cause FAD remains a hotly debated topic in the field. Because FAD is an autosomal-dominant disorder (patients carry both healthy and mutant alleles), a major unknown in the discussion remains the role of the healthy allele and, to a lesser extent, the role of the brain environment on the total (normal + mutant proteases) γ-secretase activity. To what degree do normal and mutant complexes contribute to total γ-secretase activity in the patient brain? Does the healthy allele compensate for the disease allele effects? Despite their relevance, those questions have not been addressed.Only one group, i.e., Potter et al. (2013), have estimated the Aβ production kinetics in the FAD brain by measuring isotope-labeled Aβ peptides in the cerebrospinal fluid of patients (stable isotope-labeled kinetics [SILK]). Feeding the in vivo metabolic labeling patient data into a mathematical model, specifically generated for their approach, they described higher Aβ42 production rates in the central nervous system of PSEN mutation carriers (Potter et al., 2013). Accordingly, Potter et al. (2013) suggest that increments in Aβ42 play a decisive pathogenic role in AD.In contrast, a “revised” loss-of-function (LOF) hypothesis has recently been proposed by Xia et al. (2015). In this view, loss of PSEN/γ-secretase physiological cell signaling function causes neurodegeneration, whereas changes in Aβ peptides are only secondary byproducts that arise from but do not trigger the disease (Xia et al., 2015). The idea is only tenable if FAD-linked PSEN mutations exert a LOF effect on PSEN/γ-secretase and, in addition, a dominant-negative effect on the healthy PSEN allele (normal γ-secretase) in patients, a key part of this hypothesis (Heilig et al., 2013; Xia et al., 2015). However, it should be stressed that γ-secretase haploinsufficiency caused by nonsense, frameshift, and splice site mutations in genes coding for essential subunits of γ-secretase (Nct, Pen2, and PSEN) is pathogenic in nature; such haploinsufficiency causes a chronic inflammatory disease of hair follicles known as familial acne inversa. Most importantly, no clinical association between this disorder and AD has been reported (for a review see Pink et al. [2013]). Furthermore, if FAD-linked PSEN mutations were truly LOF mutations, resulting in “inactive” γ-secretase complexes, homozygous individuals for the disease allele would not be viable because of disturbances in Notch signaling during embryonic development. However, six individuals with homozygous PSEN1 E280A gene mutation have been identified (Kosik et al., 2015).An alternative view to both hypotheses is that pathogenic mutations in PSEN cause disease by qualitative shifts in Aβ profile production (γ-secretase dysfunction; Chávez-Gutiérrez et al., 2012). We have demonstrated that loss of endopeptidase activity is not necessarily observed in γ-secretase complexes containing PSEN1/2 FAD-linked mutations, but reduced carboxypeptidase-like efficiency (γ-secretase dysfunction) is the constant denominator. Furthermore, FAD PSEN mutations may affect the carboxypeptidase-like γ-secretase activity at multiple turnovers, resulting in increased Aβ43 and Aβ42 levels as well as in other longer Aβ peptides, such as Aβ45 and Aβ46 (Quintero-Monzon et al., 2011; Chávez-Gutiérrez et al., 2012; Fernandez et al., 2014). These data support a model in which relative, rather than absolute, changes in Aβ product profiles are at the basis of PSEN/γ-secretase–mediated pathogenicity. However, these findings were based on studies conducted in PSEN1/2-deficient MEFs, which does not fully recapitulate the in vivo heterozygous situation in the FAD patient’s brain.In the current study, we investigated processing of APP by the γ-secretase complex in postmortem human brain samples from FAD and SAD patients and healthy control subjects. Our investigation is the first to directly assess γ-secretase activity in brain material from FAD mutant carriers and to address how the FAD-linked mutant heterozygous situation in patients affects γ-secretase function in brain. 相似文献
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Molecular dynamics simulations of amyloid-β (16–22) peptide dimer in water as well as at two different experimentally studied concentrations of hydrated ionic liquids (ILs), ethylammonium mesylate (EAM), ethylammonium nitrate (EAN), and triethylammonium mesylate (TEAM), were carried out employing an umbrella sampling method. We used the average Ψ angle of the peptide backbone as the reaction coordinate to observe the conformational changes of a peptide dimer. Secondary structural element values were calculated for the peptide dimer along the reaction coordinate to see the transition of the peptide dimer between β-sheet and α-helix conformations. We observe the β-sheet conformation as the global minimum on the free energy surfaces in both EAM and EAN ILs at both the concentrations and at a low concentration of TEAM. However, we observe α-helix conformation as the global minimum at a high concentration of TEAM. Our results are in good correlation with the experimental findings. We calculated the average number of intramolecular and intermolecular hydrogen bonds of α-helix and β-sheet conformations in all solutions, and they are in correlation with the secondary structure element values. To understand the peptide–IL interactions, atom–atom radial distribution functions of cation, anion, and water around amide oxygen and hydrogen atoms were calculated. The solvent-accessible surface area of the peptide dimer was calculated to understand the exposure of the peptide towards the solvent during conformational changes. Finally, van der Waals (vdW) and Coulomb interaction energies were calculated between peptide–cation, peptide–anion, and peptide–water to understand the stability of conformations in different concentrations. We find that the TEA cation has more vdW interaction energy compared to Coulomb interaction energy with peptide in 70% (w/w) TEAM, which mimics a membrane-like environment to induce α-helix conformation rather than β-sheet conformation.Molecular dynamics simulations of amyloid-β (16–22) peptide dimer at two different experimentally studied concentrations of hydrated ethylammonium mesylate, ethylammonium nitrate, and triethylammonium mesylate were carried out employing an umbrella sampling method. 相似文献
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Oluwole B. Akawa Temitayo I. Subair Opeyemi S. Soremekun Fisayo A. Olotu Mahmoud E. S. Soliman 《RSC advances》2021,11(14):8003
Recent studies have shown that inhibition of the hSIRT2 enzyme provides favorable effects in neurodegenerative diseases such as Alzheimer''s disease. Prenylated xanthone phytochemicals including α-mangostin, β-mangostin and γ-mangostin obtained from Garcinia mangostana, a well-established tropical plant, have been shown experimentally to inhibit sirtuin enzymatic activity. However, the molecular mechanism of this sirtuin inhibition has not been reported. Using comprehensive integrated computational techniques, we provide molecular and timewise dynamical insights into the structural alterations capable of facilitating therapeutically beneficial effects of these phytochemicals at the catalytic core of the hSIRT2 enzyme. Findings revealed the enhanced conformational stability and compactness of the hSIRT2 catalytic core upon binding of γ-mangostin relative to the apoenzyme and better than α-mangostin and β-mangostin. Although thermodynamic calculations revealed favorable binding of all the phytochemicals to the hSIRT2 enzyme, the presence of only hydroxy functional groups on γ-mangostin facilitated the occurrence of additional hydrogen bonds involving Pro115, Phe119, Asn168 and His187 which are absent in α-mangostin- and β-mangostin-bound systems. Per-residue energy contributions showed that van der Waals and more importantly electrostatic interactions are involved in catalytic core stability with Phe96, Tyr104 and Phe235 notably contributing π–π stacking, π–π T shaped and π–sigma interactions. Cumulatively, our study revealed the structural alterations leading to inhibition of hSIRT2 catalysis and findings from this study could be significantly important for the future design and development of sirtuin inhibitors in the management of Alzheimer''s disease.Recent studies have shown that inhibition of the hSIRT2 enzyme provides favorable effects in neurodegenerative diseases such as Alzheimer''s disease. 相似文献
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Kazuma Murakami Haruka Kato Mizuho Hanaki Yoko Monobe Ken-ichi Akagi Taiji Kawase Kenji Hirose Kazuhiro Irie 《RSC advances》2020,10(33):19506
Protein persulfidation plays a role in redox signaling as an anti-oxidant. Dimers of amyloid β42 (Aβ42), which induces oxidative stress-associated neurotoxicity as a causative agent of Alzheimer''s disease (AD), are minimum units of oligomers in AD pathology. Met35 can be susceptible to persulfidation through its substitution to homoCys residue under the condition of oxidative stress. In order to verify whether persulfidation has an effect in AD, herein we report a chemical approach by synthesizing disulfide dimers of Aβ42 and their evaluation of biochemical properties. A homoCys-disulfide dimer model at position 35 of Aβ42 formed a partial β-sheet structure, but its neurotoxicity was much weaker than that of the corresponding monomer. In contrast, the congener with an alkyl linker generated β-sheet-rich 8–16-mer oligomers with potent neurotoxicity. The length of protofibrils generated from the homoCys-disulfide dimer model was shorter than that of its congener with an alkyl linker. Therefore, the current data do not support the involvement of Aβ42 persulfidation in Alzheimer''s disease.Our data do not support the Aβ42 persulfidation hypothesis in Alzheimer''s etiology because the neurotoxicity of the homoCys-disulfide-Aβ42 dimer was very weak. 相似文献
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Xiu-Fang Huang Jian-Jun Li Yan-Gu Tao Xie-Qi Wang Ru-Lan Zhang Jia-Lin Zhang Zu-Qing Su Qi-Hui Huang Yuan-Hui Deng 《RSC advances》2018,8(34):18926
Alzheimer''s disease (AD), a neurodegenerative disorder, is marked by the accumulation of amyloid-β (Aβ) and neuroinflammation which promote the development of AD. Geniposide, the main ingredient isolated from Chinese herbal medicine Gardenia jasminoides Ellis, has a variety of pharmacological functions such as anti-apoptosis and anti-inflammatory activity. Hence, we estimated the inflammatory cytotoxicity caused by Aβ25–35 and the neuroprotective effects of geniposide in HT22 cells. In this research, following incubation with Aβ25–35 (40 μM, 24 h) in HT22 cells, the methylthiazolyl tetrazolium (MTT) and lactate dehydrogenase (LDH) release assays showed that the cell survival rate was significantly decreased. In contrast, the reactive oxygen species (ROS) assay indicated that Aβ25–35 enhanced ROS accumulation and apoptosis showed in both hoechst 33342 staining and annexin V-FITC/PI double staining. And then, immunofluorescence test revealed that Aβ25–35 promoted p65 to transfer into the nucleus indicating p65 was activated by Aβ25–35. Moreover, western blot analysis proved that Aβ25–35 increased the expression of nitric oxide species (iNOS), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2) and interleukin-1β (IL-1β). Simultaneously, Aβ25–35 also promoted the expression of toll-like receptor 4 (TLR4), p-p65 and p-IκB-α accompanied with the increase in the level of beta-secretase 1 (BACE1) and caspase-3 which further supported Aβ25–35 induced apoptosis and inflammation. Fortunately, this up-regulation was reversed by geniposide. In conclusion, our data suggest that geniposide can alleviate Aβ25–35-induced inflammatory response to protect neurons, which is possibly involved with the inhibition of the TLR4/NF-κB pathway in HT22 cells. Geniposide may be the latent treatment for AD induced by neuroinflammation and apoptosis.Alzheimer''s disease (AD), a neurodegenerative disorder, is marked by the accumulation of amyloid-β (Aβ) and neuroinflammation which promote the development of AD. 相似文献
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Mengying Wei Yuanyuan Liu Zifeng Pi Kexin Yue Shizhe Li Mingxin Hu Zhiqiang Liu Fengrui Song Zhongying Liu 《RSC advances》2019,9(32):18308
Alzheimer''s disease (AD) has become one of the major diseases endangering the health of the elderly. Clarifying the features of each AD animal model is valuable for understanding the onset and progression of diseases and developing potential treatments in the pharmaceutical industry. In this study, we aimed to clarify plasma metabolomics and neurotransmitter dysfunction in the process of AD model rat induced by amyloid beta 25-35 (Aβ 25-35). Firstly, Morris Water Maze (MWM) test was used to investigate cognitive impairment in AD rat after 2, 4 and 8 weeks of modelling. Based on this, the effects on levels of AD-related enzymes and eight neurotransmitters were analyzed. And plasma metabolomics analysis based on ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) was used to research the metabolic disturbances in the process of AD rat. The results shown the injury on the spatial learning ability of AD rats was gradually aggravated within 4 weeks, reached the maximum at 4 weeks and then was stable until 8 weeks. During 8 weeks of modeling, the levels of enzymes including β-secretase, γ-secretase, glycogen synthase kinase-3β (GSK-3β), acetyl cholinesterase (AchE) and nitric oxide synthase (NOS) were significant increased in the plasma of AD rats. The neurotransmitter dysfunction was mainly involved in γ-aminobutyric acid (GABA), acetyl choline (Ach), glutamic acid (Glu), 5-hydroxytryptamine (5-HT), dopamine (DA) and norepinephrine (NE). 17 endogenous metabolites correlated with AD were successfully detected in the metabolomics analysis. These metabolites were mainly involved in fatty acids, sphingolipids, and sterols metabolisms, vitamin metabolism, and amino acid metabolism. These metabolites might be the potential biomarkers that correctly mark different stages of AD. The study on peripheral plasma indices reflecting the process of AD laid the foundation for understand the pathophysiology of AD and find an effective and radical cure. And the rules of endogenous metabolic disorder in AD rats also have a certain guiding significance for the future study of food–drug interactions at different stages of AD.The cognitive impairment, Alzheimer''s disease (AD) related enzymes, neurotransmitters and endogenous metabolites shown a dynamic change in AD model rat induced by amyloid beta 25-35. 相似文献
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Chandra Bhushan Mishra Shruti Shalini Siddharth Gusain Amresh Prakash Jyoti Kumari Shikha Kumari Anita Kumari Yadav Andrew M. Lynn Manisha Tiwari 《RSC advances》2020,10(30):17602
A novel series of benzothiazole–piperazine hybrids were rationally designed, synthesized, and evaluated as multifunctional ligands against Alzheimer''s disease (AD). The synthesized hybrid molecules illustrated modest to strong inhibition of acetylcholinesterase (AChE) and Aβ1-42 aggregation. Compound 12 emerged as the most potent hybrid molecule exhibiting balanced functions with effective, uncompetitive and selective inhibition against AChE (IC50 = 2.31 μM), good copper chelation, Aβ1-42 aggregation inhibition (53.30%) and disaggregation activities. Confocal laser scanning microscopy and TEM analysis also validate the Aβ fibril inhibition ability of this compound. Furthermore, this compound has also shown low toxicity and is capable of impeding loss of cell viability elicited by H2O2 neurotoxicity in SHSY-5Y cells. Notably, compound 12 significantly improved cognition and spatial memory against scopolamine-induced memory deficit in a mouse model. Hence, our results corroborate the multifunctional nature of novel hybrid molecule 12 against AD and it may be a suitable lead for further development as an effective therapeutic agent for therapy in the future.A novel series of benzothiazole–piperazine hybrids were rationally designed, synthesized, and evaluated as multifunctional ligands against Alzheimer''s disease (AD). 相似文献
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The self-assembly of Amyloid beta (Aβ) peptides are widely accepted to associate with Alzheimer''s disease (AD) via several proposed mechanisms. Because Aβ oligomers exist in a complicated environment consisting of various forms of Aβ, including oligomers, protofibrils, and fibrils, their structure has not been well understood. The negatively charged residue D23 is one of the critical residues of the Aβ peptide as it is located in the central hydrophobic domain of the Aβ N-terminal and forms a salt-bridge D23-K28, which helps stabilize the loop domain. In the familial Iowa (D23N) mutant, the total net charge of Aβ oligomers decreases, resulting in the decrease of electrostatic repulsion between D23N Aβ monomers and thus the increase in their self-aggregation rate. In this work, the impact of the D23N mutation on 3Aβ11–40 trimer was characterized utilizing temperature replica exchange molecular dynamics (REMD) simulations. Our simulation reveals that D23N mutation significantly enhances the affinity between the constituting chains in the trimer, increases the β-content (especially in the sequence 21–23), and shifts the β-strand hydrophobic core from crossing arrangement to parallel arrangement, which is consistent with the increase in self-aggregation rate. Molecular docking indicates that the Aβ fibril-binding ligands bind to the D23N and WT forms at different poses. These compounds prefer to bind to the N-terminal β-strand of the D23N mutant trimer, while they mostly bind to the N-terminal loop region of the WT. It is important to take into account the difference in the binding of ligands to mutant and wild type Aβ peptides in designing efficient inhibitors for various types of AD.Amyloid beta peptide oligomers are believed to play key roles in Alzheimer''s disease pathogenesis. D23N mutation significantly changes their structure and how they bind potential inhibitors. 相似文献
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Alzheimer''s disease is linked to the aggregation of the amyloid-β protein (Aβ) of 40 or 42 amino acids. Lipid membranes are known to modulate the rate and mechanisms of the Aβ aggregation. Point mutations in Aβ can alter these rates and mechanisms. In particular, experiments show that F19 mutations influence the aggregation rate, but maintain the fibril structures. Here, we used molecular dynamics simulations to examine the effect of the F19W mutation in the 3Aβ11–40 trimer immersed in DPPC lipid bilayers submerged in aqueous solution. Substituting Phe by its closest (non-polar) aromatic amino acid Trp has a dramatic reduction in binding affinity to the phospholipid membrane (measured with respect to the solvated protein) compared to the wild type: the binding free energy of the protein–DPPC lipid bilayer increases by 40–50 kcal mol−1 over the wild-type. This is accompanied by conformational changes and loss of salt bridges, as well as a more complex free energy surface, all indicative of a more flexible and less stable mutated trimer. These results suggest that the impact of mutations can be assessed, at least partially, by evaluating the interaction of the mutated peptides with the lipid membranes.Dominant conformations of F19W 3Aβ11–40 immersed in transmembrane DPPC lipid bilayer submerged in aqueous solution. 相似文献
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Jinzhuan Wang Kun Wang Zhenzhu Zhu Yafeng He Changli Zhang Zijian Guo Xiaoyong Wang 《RSC advances》2019,9(25):14126
Alzheimer''s disease (AD) is a neurodegenerative malady associated with amyloid β-peptide (Aβ) aggregation in the brain. Metal ions play important roles in Aβ aggregation and neurotoxicity. Metal chelators are potential therapeutic agents for AD because they could sequester metal ions from the Aβ aggregates and reverse the aggregation. The blood–brain barrier (BBB) is a major obstacle for drug delivery to AD patients. Herein, a nanoscale silica–cyclen composite combining cyclen as the metal chelator and silica nanoparticles as a carrier was reported. Silica–cyclen was characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FT-IR) and dynamic light scattering (DLS). The inhibitory effect of the silica–cyclen nanochelator on Zn2+- or Cu2+-induced Aβ aggregation was investigated by using a BCA protein assay and TEM. Similar to cyclen, silica–cyclen can effectively inhibit the Aβ aggregation and reduce the generation of reactive oxygen species induced by the Cu–Aβ40 complex, thereby lessening the metal-induced Aβ toxicity against PC12 cells. In vivo studies indicate that the silica–cyclen nanochelator can cross the BBB, which may provide inspiration for the construction of novel Aβ inhibitors.A BBB-passable nanoscale silica–cyclen chelator effectively reduces the metal-induced Aβ aggregates and related ROS, thereby decreasing the neurotoxicity of Aβ. 相似文献
14.
The search for efficient inhibitors targeting Aβ oligomers and fibrils is an important issue in Alzheimer''s disease treatment. As a consequence, an accurate and computationally cheap approach to estimate the binding affinity for many ligands interacting with Aβ peptides is very important. Here, the calculated binding free energies of 30 ligands interacting with 12Aβ11–40 peptides using the linear interaction energy (LIE) approach are found to be in good correlation with experimental data (R = 0.79). The binding affinities of these complexes are also calculated by using free energy perturbation (FEP) and molecular mechanic/Poisson–Boltzmann surface area (MM/PBSA) methods. The time-consuming FEP method provides results with similar correlation (R = 0.72), whereas MM/PBSA calculations show very low correlation with experimental data (R = 0.27). In all complexes, van der Waals interactions contribute much more than electrostatic interactions. The LIE model, which is much less time-consuming than both the FEP and MM/PBSA methods, opens the door to accurate and rapid affinity prediction of ligands with Aβ peptides and the design of new ligands.The efficient approach to estimate inhibitors targeting Aβ oligomers and fibrils is an important issue in Alzheimer''s disease treatment. 相似文献
15.
The aggregation of amyloids into toxic oligomers is believed to be a key pathogenic event in the onset of Alzheimer''s disease. Peptidomimetic modulators capable of destabilizing the propagation of an extended network of β-sheet fibrils represent a potential intervention strategy. Modifications to amyloid-beta (Aβ) peptides derived from the core domain have afforded inhibitors capable of both antagonizing aggregation and reducing amyloid toxicity. Previous work from our laboratory has shown that peptide backbone amination stabilizes β-sheet-like conformations and precludes β-strand aggregation. Here, we report the synthesis of N-aminated hexapeptides capable of inhibiting the fibrillization of full-length Aβ42. A key feature of our design is N-amino substituents at alternating backbone amides within the aggregation-prone Aβ16–21 sequence. This strategy allows for maintenance of an intact hydrogen-bonding backbone edge as well as side chain moieties important for favorable hydrophobic interactions. An N-amino scan of Aβ16–21 resulted in the identification of peptidomimetics that block Aβ42 fibrilization in several biophysical assays.Structure-based design of backbone-aminated peptides affords novel β-strand mimics that inhibit amyloid-beta fibrillogenesis. 相似文献
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17.
Naoki Hasunuma Masahiro Kawakami Hirotsugu Hiramatsu Takakazu Nakabayashi 《RSC advances》2018,8(32):17847
We have shown that fullerene (C60) becomes soluble in water by mixing fullerene and amyloid β peptide (Aβ40) whose fibril structures are considered to be associated with Alzheimer''s disease. The water-solubility of fullerene arises from the generation of a nanosized complex between fullerene and the monomer species of Aβ40 (Aβ40-C60). The prepared Aβ40-C60 exhibits photo-induced activity with visible light to induce the inhibition of Aβ40 fibrillation and the cytotoxicity for cultured HeLa cells. The observed photo-induced phenomena result from the generation of singlet oxygen via photoexcitation, inducing oxidative damage to Aβ40 and HeLa cells. The oxidized Aβ40 following photoexcitation of Aβ40-C60 was confirmed by mass spectrometry.We have shown that fullerene (C60) becomes soluble in water by mixing fullerene and amyloid β peptide (Aβ40) whose fibril structures are considered to be associated with Alzheimer''s disease. 相似文献
18.
Zhengyang Duan Mingyao Song Tianguo Li Shuli Liu Xiaojun Xu Ronggao Qin Changhua He Yao Wang Longqian Xu Mengjiao Zhang 《RSC advances》2018,8(55):31542
In this study, a crosslinked yeast/β-cyclodextrin polymer (Y–β-CDP), for use as an effective adsorbent for removal Pb(ii) and Cd(ii) ions from aqueous solution, has been innovatively prepared by grafting β-cyclodextrin (β-CD) onto the surface of baker''s yeast (BY) and thiomalic acid as a crosslinker. Several characterization techniques, such as SEM equipped with an EDS analyzer, FTIR, XRD, and XPS were employed characterize the Y–β-CDP. The impact of various operating parameters, such as pH, adsorbent dosage, initial concentration of metal ions, contact time and solution temperature, as well as adsorption kinetics, isotherms and thermodynamics were systematically investigated. The adsorption of Pb(ii) and Cd(ii) on Y–β-CDP reached equilibrium in 25 min, and the kinetic process conforms to the pseudo-second order model. The Langmuir model was used to describe the adsorption isotherm data better than the Freundlich model. The predicted maximum adsorption capacity at 25 °C for Pb(ii) and Cd(ii) was 150.08 and 102.80 mg g−1, respectively, when the initial concentration of metal ions was 120 mg L−1. The thermodynamic analysis revealed that the adsorption procedure of Pb(ii) and Cd(ii) onto Y–β-CDP was spontaneous and endothermic. Furthermore, regeneration experiments demonstrated that Y–β-CDP had excellent recyclability. Together, all results suggested that Y–β-CDP could potentially be a promising adsorbent in the purification of water contaminated with heavy metal ions.A cross-linked yeast/β-cyclodextrin polymer (Y–β-CDP) was synthesized to remove Pb(ii) and Cd(ii) from aqueous solution. 相似文献
19.
Graphyne was recently facilely synthesized with superior mechanical and electrical performance. We investigate the ballistic protection properties of α-, β-, δ-, and γ-graphyne sheets using molecular dynamics simulations in conjunction with elastic theory. The velocities of the in-plane elastic wave and out-of-plane cone wave are obtained by both membrane theory and molecular dynamics simulations. The specific penetration energies are approximately 83% that of graphene, indicating high impact resistance. γ-Graphyne has high sound wave speeds comparable to those of graphene, and its Young''s modulus is approximately 60% that of graphene. δ-Graphyne has the highest cone wave speed among the four structures, while α-graphyne possesses the highest penetration energy and impact resistance at most tested projectile speeds. Our results indicate that graphyne is a good protective structural material.Graphyne was recently facilely synthesized with superior mechanical and electrical performance. 相似文献
20.
Nasimudeen R. Jabir Md. Tabish Rehman Khadeejah Alsolami Shazi Shakil Torki A. Zughaibi Raed F. Alserihi Mohd. Shahnawaz Khan Mohamed F. AlAjmi Shams Tabrez 《Annals of medicine》2021,53(1):2332
IntroductionAlzheimer''s disease (AD), the most predominant cause of dementia, has evolved tremendously with an escalating frequency, mainly affecting the elderly population. An effective means of delaying, preventing, or treating AD is yet to be achieved. The failure rate of dementia drug trials has been relatively higher than in other disease-related clinical trials. Hence, multi-targeted therapeutic approaches are gaining attention in pharmacological developments.AimsAs an extension of our earlier reports, we have performed docking and molecular dynamic (MD) simulation studies for the same 13 potential ligands against beta-site APP cleaving enzyme 1 (BACE-1) and γ-secretase as a therapeutic target for AD. The In-silico screening of these ligands as potential inhibitors of BACE-1 and γ-secretase was performed using AutoDock enabled PyRx v-0.8. The protein-ligand interactions were analyzed in Discovery Studio 2020 (BIOVIA). The stability of the most promising ligand against BACE-1 and γ-secretase was evaluated by MD simulation using Desmond-2018 (Schrodinger, LLC, NY, USA).ResultsThe computational screening revealed that the docking energy values for each of the ligands against both the target enzymes were in the range of −7.0 to −10.1 kcal/mol. Among the 13 ligands, 8 (55E, 6Z2, 6Z5, BRW, F1B, GVP, IQ6, and X37) showed binding energies of ≤−8 kcal/mol against BACE-1 and γ-secretase. For the selected enzyme targets, BACE-1 and γ-secretase, 6Z5 displayed the lowest binding energy of −10.1 and −9.8 kcal/mol, respectively. The MD simulation study confirmed the stability of BACE-6Z5 and γ-secretase-6Z5 complexes and highlighted the formation of a stable complex between 6Z5 and target enzymes.ConclusionThe virtual screening, molecular docking, and molecular dynamics simulation studies revealed the potential of these multi-enzyme targeted ligands. Among the studied ligands, 6Z5 seems to have the best binding potential and forms a stable complex with BACE-1 and γ-secretase. We recommend the synthesis of 6Z5 for future in-vitro and in-vivo studies. 相似文献