Alzheimer's Beta-amyloid Peptide Research Articles

Expression of concern: A molecular dynamic approach to a hypothesis on the dynamical behavior of Rosuvastatin on Alzheimer's disease Amyloid beta-peptide interactions in the atomic structures

Expression of concern: A molecular dynamic approach to a hypothesis on the dynamical behavior of Rosuvastatin on Alzheimer's disease Amyloid beta-peptide interactions in the atomic structures

Hippocampal protein interaction with Alzheimer's amyloid beta peptide: 14–3-3 zeta and Tubulin beta promote tau phosphorylation

Hippocampal protein interaction with Alzheimer's amyloid beta peptide: 14–3-3 zeta and Tubulin beta promote tau phosphorylation

In silico study of traditional Chinese medicinal compounds targeting alzheimer's disease amyloid beta-peptide (1–42)

The objective of this study is to recognize the potential traditional Chinese medicinal compound by virtual screening and docking analysis for the amyloid-beta disaggregation mechanism on Alzheimer's disease management. The selected target PDB ID: 1IYT was retrieved from protein data bank database. By uploading an optimized target structure in iScreen virtual screening tool, traditional Chinese medicinal compounds were shortlisted based on scoring functions. The resulted three common compounds were subjected to druglikeness, ADMET prediction and Autodock Vina analysis using Molinspiration, pkCSM and PyRx tool respectively. By considering all the results obtained in filter analysis, the ligand sanggenol A was shortlisted. The energy minimized ligand sanggenol A structure was docked against the optimized amyloid-beta peptide solution structure using Autodock 4.2.6 software. The binding energies for ten conformations of docked sanggenol A - beta amyloid complex is reported. Among ten conformations, three topmost conformations having better binding energies are interpreted with hydrophobic, hydrophilic, pi-pi and pi-cation interactions. Based on these scientific evidences, in silico study approach concludes that sanggenol A as a promising lead candidate which can be carried out for the further preclinical and clinical studies to prove for the management of Alzheimer's disease.

A molecular dynamic approach to a hypothesis on the dynamical behavior of Rosuvastatin on Alzheimer's disease amyloid beta-peptide interactions in the atomic structures

The amyloid-beta peptide is a peptide that consists of 42 amino acids and is derived from the precursor protein known as an amyloid-beta precursor protein (APP). The amyloid-beta precursor protein is a glycoprotein that is a single-pass transmembrane transporter that only crosses the membrane once. On chromosome 21, you will find the gene that codes for amyloid-beta precursor protein. Because of its significance in biological applications, the protein's thermal characteristics is being investigated. The thermal behavior of this biostructure may be predicted using computer models, which are dependent on the structure's arrangement of atoms. Numerical molecular dynamics techniques (the Green-Kubo approach), the thermal behavior of amyloid beta-peptide is computed in the present computational work. In this approach, amyloid beta-peptide is formed by the atoms C, F, H, N, O, and S using the DREIDING and Universal force field (UFF). According to the findings of our MD simulations, the amyloid-beta protein has a thermal conductivity (k) of 1.23 W/mK under typical conditions ( T = 300 K and P = 1 bar). Simulations have also shown that the starting temperature and pressure significantly impact how the modeled protein reacts to heat. After t = 10 ns, thermal behavior is seen in the simulated structures, brought about by a rise in the starting temperature and pressure.

Error-prone protein synthesis recapitulates early symptoms of Alzheimer disease in aging mice.

Age-related neurodegenerative diseases (NDDs) are associated with the aggregation and propagation of specific pathogenic protein species (e.g., Aβ, α-synuclein). However, whether disruption of synaptic homeostasis results from protein misfolding per se rather than accumulation of a specific rogue protein is an unexplored question. Here, we show that error-prone translation, with its frequent outcome of random protein misfolding, is sufficient to recapitulate many early features of NDDs, including perturbed Ca2+ signaling, neuronal hyperexcitability, and mitochondrial dysfunction. Mice expressing the ribosomal ambiguity mutation Rps9 D95N exhibited disrupted synaptic homeostasis resulting in behavioral changes reminiscent of early Alzheimer disease (AD), such as learning and memory deficits, maladaptive emotional responses, epileptiform discharges, suppressed circadian rhythmicity, and sleep fragmentation, accompanied by hippocampal NPY expression and cerebral glucose hypometabolism. Collectively, our findings suggest that random protein misfolding may contribute to the pathogenesis of age-related NDDs, providing an alternative framework for understanding the initiation of AD.

Graphene based electrochemical immunosensor for the ultra-sensitive label free detection of Alzheimer's beta amyloid peptides Aβ(1-42).

An immunosensor capable of high sensitivity detection of beta-amyloid peptides, shown to be a reliable biomarker for Alzheimer's disease, has been developed using screen printed graphene electrodes (SPGEs) modified with ultra-thin layers of polymerised 1,5-diaminonaphthalene (pDAN). Electropolymerization of 1,5-diaminonaphthalene (DAN) was performed to coat the graphene screen printed electrodes in a continuous polymer layer with controlled thickness. The surface characteristics of pristine graphene and polymer modified graphene electrodes were examined using Raman and X-ray photoelectron spectroscopy. The effects of polymer thickness on the electron transfer rates were investigated. An immunosensor for selective detection of beta amyloid peptides Aβ(1–42) was developed via biofunctionalization of the pDAN modified SPGE with the anti-beta amyloid antibody used as the peptide bioreceptor. The immunosensor has been used for specific detection of Aβ(1–42) with a linear range of 1 pg mL−1 to 1000 pg mL−1 and showed 1.4 pg mL−1 and 4.25 pg mL−1 detection and quantification limit, respectively. The biosensor was further validated for the analysis of spiked human plasma. The immunosensor enables rapid, accurate, precise, reproducible and highly sensitive detection of Aβ(1–42) using a low-cost SPGE platform, which opens the possibilities for diagnostic ex vivo applications and research-based real time studies.

Cu2+ Effects on Beta-Amyloid Oligomerisation Monitored by the Fluorescence of Intrinsic Tyrosine.

A non-invasive intrinsic fluorescence sensing of the early stages of Alzheimer's beta amyloid peptide aggregation in the presence of copper ions is reported. By using time-resolved fluorescence techniques the formation of beta amyloid-copper complexes and the accelerated peptide aggregation are demonstrated. The shifts in the emission spectral peaks indicate that the peptides exhibit different aggregation pathways than in the absence of copper.

Importance of time-ordered non-uniform sampling of multi-dimensional NMR spectra of Aβ1-42 peptide under aggregating conditions.

Although the order of the time steps in which the non-uniform sampling (NUS) schedule is implemented when acquiring multi-dimensional NMR spectra is of limited importance when sample conditions remain unchanged over the course of the experiment, it is shown to have major impact when samples are unstable. In the latter case, time-ordering of the NUS data points by the normalized radial length yields a reduction of sampling artifacts, regardless of the spectral reconstruction algorithm. The disadvantage of time-ordered NUS sampling is that halting the experiment prior to its completion will result in lower spectral resolution, rather than a sparser data matrix. Alternatively, digitally correcting for sample decay prior to reconstruction of randomly ordered NUS data points can mitigate reconstruction artifacts, at the cost of somewhat lower sensitivity. Application of these sampling schemes to the Alzheimer's amyloid beta (Aβ1-42) peptide at an elevated concentration, low temperature, and 3 kbar of pressure, where approximately 75% of the peptide reverts to an NMR-invisible state during the collection of a 3D 15N-separated NOESY spectrum, highlights the improvement in artifact suppression and reveals weak medium-range NOE contacts in several regions, including the C-terminal region of the peptide.

Amyloid-β fibrils assembled on ganglioside-enriched membranes contain both parallel β-sheets and turns

Some protein and peptide aggregates, such as those of amyloid-β protein (Aβ), are neurotoxic and have been implicated in several neurodegenerative diseases. Aβ accumulates at nanoclusters enriched in neuronal lipids called gangliosides in the presynaptic neuronal membrane, and the resulting oligomeric and/or fibrous forms accelerate the development of Alzheimer's disease. Although the presence of Aβ deposits at such nanoclusters is known, the mechanism of their assembly and the relationship between Aβ secondary structure and topography are still unclear. Here, we first confirmed by atomic force microscopy that Aβ40 fibrils can be obtained by incubating seed-free Aβ40 monomers with a membrane composed of sphingomyelin, cholesterol, and the ganglioside GM1. Using Fourier transform infrared (FTIR) reflection-absorption spectroscopy, we then found that these lipid-associated fibrils contained parallel β-sheets, whereas self-assembled Aβ40 molecules formed antiparallel β-sheets. We also found that the fibrils obtained at GM1-rich nanoclusters were generated from turn Aβ40 Our findings indicate that Aβ generally self-assembles into antiparallel β-structures but can also form protofibrils with parallel β-sheets by interacting with ganglioside-bound Aβ. We concluded that by promoting the formation of parallel β-sheets, highly ganglioside-enriched nanoclusters help accelerate the elongation of Aβ fibrils. These results advance our understanding of ganglioside-induced Aβ fibril formation in neuronal membranes and may help inform the development of additional therapies for Alzheimer's disease.

Nanodisc-Forming Scaffold Protein Promoted Retardation of Amyloid-Beta Aggregation

Peptidic nanodiscs are useful membrane mimetic tools for structural and functional studies of membrane proteins, and membrane interacting peptides including amyloids. Here, we demonstrate anti-amyloidogenic activities of a nanodisc-forming 18-residue peptide (denoted as 4F), both in lipid-bound and lipid-free states by using Alzheimer's amyloid-beta (Aβ40) peptide as an example. Fluorescence-based amyloid fibrillation kinetic assays showed a significant delay in Aβ40 amyloid aggregation by the 4F peptide. In addition, 4F-encased lipid nanodiscs, at an optimal concentration of 4F (>20 μM) and nanodisc size (<10 nm), significantly affect amyloid fibrillation. A comparison of experimental results obtained from nanodiscs with that obtained from liposomes revealed a substantial inhibitory efficacy of 4F-lipid nanodiscs against Aβ40 aggregation and were also found to be suitable to trap Aβ40 intermediates. A combination of atomistic molecular dynamics simulations with NMR and circular dichroism experimental results exhibited a substantial change in Aβ40 conformation upon 4F binding through electrostatic and π–π interactions. Specifically, the 4F peptide was found to interfere with the central β-sheet-forming residues of Aβ40 through substantial hydrogen, π–π, and π–alkyl interactions. Fluorescence experiments and coarse-grained molecular dynamics simulations showed the formation of a ternary complex, where Aβ40 binds to the proximity of peptidic belt and membrane surface that deaccelerate amyloid fibrillation. Electron microscopy images revealed short and thick amyloid fibers of Aβ40 formed in the presence of 4F or 4F-lipid nanodsics. These findings could aid in the development of amyloid inhibitors as well as in stabilizing Aβ40 intermediates for high-resolution structural and neurobiological studies.

Effect of Hyperglycemic Conditions on the Early Self-Assembly of the Alzheimer's Amyloid Beta Peptide: Implications for Neurotoxicity

Effect of Hyperglycemic Conditions on the Early Self-Assembly of the Alzheimer's Amyloid Beta Peptide: Implications for Neurotoxicity

Antiaggregation Potential of Padina gymnospora against the Toxic Alzheimer's Beta-Amyloid Peptide 25-35 and Cholinesterase Inhibitory Property of Its Bioactive Compounds.

Inhibition of β-amyloid (Aβ) aggregation in the cerebral cortex of the brain is a promising therapeutic and defensive strategy in identification of disease modifying agents for Alzheimer’s disease (AD). Since natural products are considered as the current alternative trend for the discovery of AD drugs, the present study aims at the evaluation of anti-amyloidogenic potential of the marine seaweed Padina gymnospora. Prevention of aggregation and disaggregation of the mature fibril formation of Aβ 25–35 by acetone extracts of P. gymnospora (ACTPG) was evaluated in two phases by Thioflavin T assay. The results were further confirmed by confocal laser scanning microscopy (CLSM) analysis and Fourier transform infrared (FTIR) spectroscopic analysis. The results of antiaggregation and disaggregation assay showed that the increase in fluorescence intensity of aggregated Aβ and the co-treatment of ACTPG (250 μg/ml) with Aβ 25–35, an extensive decrease in the fluorescence intensity was observed in both phases, which suggests that ACTPG prevents the oligomers formation and disaggregation of mature fibrils. In addition, ACTPG was subjected to column chromatography and the bioactivity was screened based on the cholinesterase inhibitory activity. Finally, the active fraction was subjected to LC-MS/MS analysis for the identification of bioactive compounds. Overall, the results suggest that the bioactive compound alpha bisabolol present in the alga might be responsible for the observed cholinesterase inhibition with the IC50 value < 10 μg/ml for both AChE and BuChE when compared to standard drug donepezil (IC50 value < 6 μg/ml) and support its use for the treatment of neurological disorders.

Computational Insights into Substrate and Site Specificities, Catalytic Mechanism, and Protonation States of the Catalytic Asp Dyad of β -Secretase.

In this review, information regarding substrate and site specificities, catalytic mechanism, and protonation states of the catalytic Asp dyad of β-secretase (BACE1) derived from computational studies has been discussed. BACE1 catalyzes the rate-limiting step in the generation of Alzheimer amyloid beta peptide through the proteolytic cleavage of the amyloid precursor protein. Due to its biological functioning, this enzyme has been considered as one of the most important targets for finding the cure for Alzheimer's disease. Molecular dynamics (MD) simulations suggested that structural differences in the key regions (inserts A, D, and F and the 10s loop) of the enzyme are responsible for the observed difference in its activities towards the WT- and SW-substrates. The modifications in the flap, third strand, and insert F regions were found to be involved in the alteration in the site specificity of the glycosylphosphatidylinositol bound form of BACE1. Our QM and QM/MM calculations suggested that BACE1 hydrolyzed the SW-substrate more efficiently than the WT-substrate and that cleavage of the peptide bond occurred in the rate-determining step. The results from molecular docking studies showed that the information concerning a single protonation state of the Asp dyad is not enough to run an in silico screening campaign.

Bapineuzumab captures the N-terminus of the Alzheimer's disease amyloid-beta peptide in a helical conformation

Bapineuzumab is a humanized antibody developed by Pfizer and Johnson & Johnson targeting the amyloid (Aβ) plaques that underlie Alzheimer's disease neuropathology. Here we report the crystal structure of a Fab-Aβ peptide complex that reveals Bapineuzumab surprisingly captures Aβ in a monomeric helical conformation at the N-terminus. Microscale thermophoresis suggests that the Fab binds soluble Aβ(1–40) with a KD of 89 (±9) nM. The structure explains the antibody's exquisite selectivity for particular Aβ species and why it cannot recognize N-terminally modified or truncated Aβ peptides.

Elucidating the catalytic mechanism of β-secretase (BACE1): A quantum mechanics/molecular mechanics (QM/MM) approach

In this quantum mechanics/molecular mechanics (QM/MM) study, the mechanisms of the hydrolytic cleavage of the Met2-Asp3 and Leu2-Asp3 peptide bonds of the amyloid precursor protein (WT-substrate) and its Swedish mutant (SW) respectively catalyzed by β-secretase (BACE1) have been investigated by explicitly including the electrostatic and steric effects of the protein environment in the calculations. BACE1 catalyzes the rate-determining step in the generation of Alzheimer amyloid beta peptides and is widely acknowledged as a promising therapeutic target. The general acid-base mechanism followed by the enzyme proceeds through the following two steps: (1) formation of the gem-diol intermediate and (2) cleavage of the peptide bond. The formation of the gem-diol intermediate occurs with the barriers of 19.6 and 16.1kcal/mol for the WT- and SW-substrate respectively. The QM/MM energetics predict that with the barriers of 21.9 and 17.2kcal/mol for the WT- and SW-substrate respectively the cleavage of the peptide bond occurs in the rate-determining step. The computed barriers are in excellent agreement with the measured barrier of ∼18.0kcal/mol for the SW-substrate and in line with the experimental observation that the cleavage of this substrate is sixty times more efficient than the WT-substrate.

Cholesterol accelerates the binding of Alzheimer's β-amyloid peptide to ganglioside GM1 through a universal hydrogen-bond-dependent sterol tuning of glycolipid conformation

Age-related alterations of membrane lipids in brain cell membranes together with high blood cholesterol are considered as major risk factors for Alzheimer's disease. Yet the molecular mechanisms by which these factors increase Alzheimer's risk are mostly unknown. In lipid raft domains of the plasma membrane, neurotoxic Alzheimer's beta-amyloid (Abeta) peptides interact with both cholesterol and ganglioside GM1. Recent data also suggested that cholesterol could stimulate the binding of Abeta to GM1 through conformational modulation of the ganglioside headgroup. Here we used a combination of physicochemical and molecular modeling approaches to decipher the mechanisms of cholesterol-assisted binding of Abeta to GM1. With the aim of decoupling the effect of cholesterol on GM1 from direct Abeta-cholesterol interactions, we designed a minimal peptide (Abeta5-16) containing the GM1-binding domain but lacking the amino acid residues involved in cholesterol recognition. Using the Langmuir technique, we showed that cholesterol (but not phosphatidylcholine or sphingomyelin) significantly accelerates the interaction of Abeta5-16 with GM1. Molecular dynamics simulations suggested that Abeta5-16 interacts with a cholesterol-stabilized dimer of GM1. The main structural effect of cholesterol is to establish a hydrogen-bond between its own OH group and the glycosidic-bond linking ceramide to the glycone part of GM1, thereby inducing a tilt in the glycolipid headgroup. This fine conformational tuning stabilizes the active conformation of the GM1 dimer whose headgroups, oriented in two opposite directions, form a chalice-shaped receptacle for Abeta. These data give new mechanistic insights into the stimulatory effect of cholesterol on Abeta/GM1 interactions. They also support the emerging concept that cholesterol is a universal modulator of protein-glycolipid interactions in the broader context of membrane recognition processes.

Simulations of Protein Aggregation

A number of diseases, known as amyloid diseases, are associated with pathological protein folding. Incorrectly or partially folded peptides or proteins can self-assemble into a variety of neurotoxic aggregate species, ranging from small soluble oligomers to amyloid fibrils. I will discuss fully atomic simulations of the early stages of aggregation of the Alzheimer Amyloid-beta peptide implicated in Alzheimer's Disease. I will also introduce an off-lattice coarse-grained peptide model that can be used to simulate the entire aggregation process from monomers to fibrils. The effects of surfaces on the morphology of the aggregates will be discussed.

Glycosaminoglycan model polymers with Poly(γ-glutamate) backbone to inhibit aggregation of β-Amyloid peptide

The glycosaminoglycan model polymers with poly-γ-glutamate backbone were synthesized by conjugation with a p-aminophenyl 6-sulfo-β-GlcNAc or taurine. Poly-γ-glutamate with 6-sulfo-β-GlcNAc exhibited the inhibition activity on aggregation of Alzheimer amyloid beta peptide(1–40). On the other hand, the polymer with taurine didn't show the inhibitory activity on aggregation of amyloid beta peptide and rather accelerated the aggregation.

Protonation States of the Catalytic Dyad of β-Secretase (BACE1) in the Presence of Chemically Diverse Inhibitors: A Molecular Docking Study

In this molecular docking study, the protonation states of the catalytic Asp dyad of the beta-secretase (BACE1) enzyme in the presence of eight chemically diverse inhibitors have been predicted. BACE1 catalyzes the rate-determining step in the generation of Alzheimer amyloid beta peptides and is widely considered as a promising therapeutic target. All the inhibitors were redocked into their corresponding X-ray structures using a combination of eight different protonation states of the Asp dyad for each inhibitor. Five inhibitors were primarily found to favor two different monoprotonated states, and the remaining three favor a dideprotonated state. In addition, five of them exhibited secondary preference for a diprotonated state. These results show that the knowledge of a single protonation state of the Asp dyad is not sufficient to search for the novel inhibitors of BACE1 and the most plausible state for each inhibitor must be determined prior to conducting in-silico screening.

Dimerization of the Full-Length Alzheimer Amyloid β-Peptide (Aβ42) in Explicit Aqueous Solution: A Molecular Dynamics Study

In this study, the mechanism of dimerization of the full-length Alzheimer amyloid beta (Aβ42) peptide and structural properties of the three most stable dimers have been elucidated through 0.8 μs classical molecular dynamics (MD) simulations. The Aβ42 dimer has been reported to be the smallest neurotoxic species that adversely affects both memory and synaptic plasticity. On the basis of interactions between the distinct regions of the Aβ42 monomer, 10 different starting configurations were developed from their native folded structures. However, only six of them were found to form dimers and among them the three most stable (X(P), C-C(AP), and N-N(P)) were chosen for the detailed analysis. The structural properties of these dimers were compared with the available experimental and theoretical data. The MD simulations show that hydrophobic regions of both monomers play critical roles in the dimerization process. The high content of the α-helical structure in all the dimers is in line with its experimentally proposed role in the oligomerization. The formation of a zipper-like structure in X(P) is also in accordance with its existence in the aggregates of several short amyloidogenic peptides. The computed values of translational (D(T)) and rotational (D(R)) diffusion constants of 0.63 × 10(-6) cm(2)/s and 0.035 ns(-1), respectively, for this dimer are supported by the corresponding values of the Aβ42 monomer. These simulations have also elucidated several other key structural properties of these peptides. This information will be very useful to design small molecules for the inhibition and disruption of the critical Aβ42 dimers.