Metal-amyloid-β peptide interactions: a preliminary investigation of molecular mechanisms for Alzheimer''''s disease

Although humans have spent exactly 100 years combating Alzheimer's disease (AD), the molecular mechanisms of AD remain unclear. Owing to the rapid growth of the oldest age groups of the population and the continuous increase of the incidence of AD, it has become one of the crucial problems to modern sciences. It would be impossible to prevent or reverse AD at the root without elucidating its molecular mechanisms. From the point of view of metal-amyloid-β peptide (Aβ) interactions, we review the molecular mechanisms of AD, mainly including Cu2 and Zn2 inducing the aggregation of Aβ, catalysing the production of active oxygen species from Aβ, as well as interacting with the ion-channel-like structures of Aβ. Moreover, the development of therapeutic drugs on the basis of metal-Aβ interactions is also briefly introduced. With the increasingly rapid progress of the molecular mechanisms of AD, we are now entering a new dawn that promises the delivery of revolutionary developments for the control of dementias.     

Study of the interaction of unaggregated and aggregated amyloid β protein (10-21) with outward potassium channel

Metal ion-induced aggregation of Aβ into insoluble plaques is a central factor in Alzheimer’s disease. Zn2 is the only physiologically available transition metal ion responsible for aggregating Aβ at pH 7.4. To make it clear that the neurotoxicity of Zn2 -induced aggregation of Aβ on neurons is the key to un- derstand Aβ mechanism of action further. In this paper, we choose Aβ (10-21) as the model fragment to research hippocampal CA1 pyramidal neurons. For the first time, we adopt the combination of spectral analysis with patch-clamp technique for the preliminary study of the mutual relations of Zn2 , Aβ and ion channel from the cell level. The following expounds upon the effects and mode of action of two forms (unaggregated and aggregated) of Aβ (10-21) on hippocampus outward potassium channel three processes (activation, inactivation and reactivation). It also shows the molecular mechanics of AD from the channel level. These results are significant for the further study of Aβ nosogenesis and the devel- opment of new types of target drugs for the treatment of AD.     

Detection of amyloid-beta by Fmoc-KLVFF self-assembled fluorescent nanoparticles for Alzheimer's disease diagnosis

The abnormal aggregation of amyloid-beta(Aβ) has been widely believed to play an important role in the pathogenesis of Alz heimer's disease(AD),which is also recognized as one of the main biomarkers for AD diagnosis.The peptide sequence Lys-Leu-Val-Phe-Phe(KLVFF) is considered as the main driver of the fibrillation of Aβ,which also can be utilized to target Aβ and inhibit its aggregation.In this study,KLVFF and Fmoc-KLVFF fluorescent nanoparticles were self-assembled through zinc coordination and π-πstacking.The recognition of Aβ aggregates including oligomers and fibrils by fluorescent nanoparticles can be realized through aromatic,hydrophobic,and hydrogen-bond interactions.The fluorescent nanoprobes can distinguish Aβ aggregation formats and detect Aβ at the limit of 1 pg/mL(S/N=3).Hence,the detection of Aβ aggregates by fluorescent peptide nanoparticles has great potential for AD diagnosis and progression prediction.     

A β-sheet-targeted theranostic agent for diagnosing and preventing aggregation of pathogenic peptides in Alzheimer's disease

Amyloid-β peptide(Aβ) aggregates, particularly Aβ oligomers, are established biomarker and toxic species in Alzheimer's disease(AD). Early detection and disaggregation of Aβ aggregates are of great importance for the treatment of AD due to the unavailability of therapy at the advanced stages of the disease. A multitalented agent, 2-{2-[(1 H-benzoimidazol-2-yl)methoxy]phenyl}benzothiazole(BPB), is designed by merging two β-sheet targeting groups into one molecule to detect and inhibit the Aβaggregation. BPB can quantitatively measure the β-sheet level of soluble Aβ oligomers and specifically distinguish the aggregates of Aβ40 and Aβ42 by unique luminescence spectrum. Animal tests demonstrate that BPB can efficiently penetrate the blood brain barrier and precisely stain Aβ plaques in the brain; more importantly, it can differentiate the blood of APP transgenic mice from that of normal ones. In addition to the diagnostic potential, BPB also suppresses the generation of ROS, protects the neurons from neurotoxicity, and disaggregates the Aβ aggregates in brain homogenates of APP transgenic mice induced by metal ions or self-assembly. In view of its detective ability toward Aβ oligomers and inhibition to Aβ-related neurotoxicity, BPB may be developed into a sensitive probe for screening blood samples in the early diagnosis of AD as well as an effective inhibitor for diminishing Aβ aggregates in the treatment of the disease.     

Aβ-binding molecules: Possible application as imaging probes and as anti-aggregation agents

As amyloid β (Aβ) is at the centre of pathogenesis of Alzheimer's disease (AD), Aβ aggregate-specific probes for in vivo studies of Aβ are potentially important for the early diagnosis and the assessment of new treatment strategies in the AD brain by noninvasive imaging. Several series of compounds derived from Congo red (CR) and Thioflavin T (ThT) have been evaluated as potential probes for the Aβ imaging. They include a diversity of core structures contributing to their affinities to Aβ. Small-molecule inhibi- tors were known to inhibit the formation of Aβ oligomers and fibrils. This inhibition has to be performed in such a way that these inhibitors bind to Aβ in the binding channel where Aβ-binding probes should sit. Therefore, several of them were used as novel core structures to develop Aβ probes, with their de- rivatives exhibiting good Aβ affinities. This approach will facilitate the design of a variety of candidates for Aβ probe molecules and anti-aggregation-therapeutic drugs. Moreover, the finding of Aβ probes with diverse core structures recognized by binding sites on Aβs will likely provide a promising per- spective for the design of 99mTc-labeled probe-derived molecules.     

Visualizing Aβdeposits in live young AD model mice with a simple red/near-infrared-fluorescent AIEgen

Precise and early detection ofβ-amyloid(Aβ)deposits in situ and in real time is pivotal to the diagnosis and early intervention of Alzheimer’s disease(AD).Optical imaging stands out to be a promising technique for such a task;however,it still remains a big challenge,due to the lack of high-performance imaging contrast agent.Restricted by poor blood-brain barrier(BBB)penetrability,short-wavelength excitation and emission,as well as the aggregation-caused quenching effect,the widely used goldstandard probes cannot be used for early in-vivo imaging of Aβdeposits.Herein,we integrate the Aβdeposits-favored geometry,amphiphilic and zwitterionic molecular structure,extended D-π-A electronic structure,and 3 D conformation into one molecule,facilely establishing a simple and economic imaging contrast agent that enjoys high specificity and affinity to Aβdeposits,good BBB penetrability,bright red/near-infrared fluorescence,low interference from autofluorescence,aggregation-induced emission(AIE)feature,high signal-to-noise ratio(SNR),and high contrast.In-vitro,ex-vivo,and in-vivo experiments with different strains of mice indicate that AIE-CNPy-AD holds the universality to Aβdeposits identification.Noteworthily,AIE-CNPy-AD is even able to precisely trace the small and sparsely-distributed Aβdeposits in AD model mice as young as 4-month-old APP/PS1 mice,the youngest having Aβdeposits.Moreover,the present probe could clearly reveal the increase and enlargement of Aβdeposits as the mice grow.Therefore,AIE-CNPy-AD might be an ideal alternative for early AD diagnosis and highly reliable monitoring of AD progression.     

Study of the interaction of Zn^2＋ with Aβ（10-21） by fluorescamine assay

Zinc may play a role as a co-factor in the pathogenesis of Alzheimer's disease(AD)through influencing the conformation and neurotoxicity of amyloidβ-protein(Aβ).Using the fluorescamine assay,we show for the first time that Zn~(2 )induced Aβ(10-21) aggregate in a concentration-dependent manner.These results indicate that Aβ(10-21)can be used as an in vitro model in Zn~(2 )- induced Aβaggregation and that the region 10-21 to be the minimal fragment of zinc-binding domain of full length Aβ(1-42).     

Synthesis and Characterization of Donor-Acceptor-Donor Triads Containing Tetrathiafulvalene and Naphthalene Diimide Units： Towards Regulation of the Intermolecular Charge-Transfer Interaction by Varying the Attached Side Groups

Introduction Extensive studies have been performed on electron donor-acceptor supramolecular systems, which have been used as models to investigate charge-transfer interactions,1 photoinduced electron and energy transfer reactions (for understanding the natural photosynthesis mechanisms).2 In recent years, molecular devices such as molecular shuttles and molecular switches based on electron donor-acceptor supramolecules have been proposed and studied.3 Since the synthesis of tetrathiafulvalene…     

Comparation of Activity against Aβ Aggregation between RR and LPFFD

Here, we introduce the design of the structure of RR(RYYAAFFARR), an inhibitor of Aβ aggregation, using molecular docking, and compare the inhibitory ability between RR and LPFFD, which interacts with Aβ mainly depending on hydrophobic interaction. Our results showed that RR which can target multiple regions of Aβ with multiple weak interactions is better than those that only target a single region with the single driving force mainly.     

Exploring the binding mechanism of thioflavin-T to the β-amyloid peptide by blind docking method

Using blind dock method,we find that thioflavin-T(ThT) can bind to both monomers and fibrils of the full-length β-amyloid peptide(Aβ1-42) and has a higher binding affinity to the fibrils.It is shown that the hydrophobic interaction between the ligand(ThT) and substrate(Aβ1-42) are stronger than hydrogen bonds.Furthermore,ThT tends to be located near the C-terminus of Aβ monomer through hydrophobic and electrostatic interactions,while it tends to contact the residues Met35 and Gly27 of the fibril surface mainly through hydrophobic interaction.Finally,according to the docking results and ThT fluorescence assay,a kinetic equation is proposed to deduce the aggregation rate coefficient of Aβ1-42.     

New progress in active immunotherapy targeting to amyloid beta

Alzheimer's disease(AD) is one of the most common types of dementia whose hallmarks include neurofibrillary tangles and senile plaques. The latter are mainly composed of amyloid-β proteins(Aβ), and it's suggested that Aβ may be the causative factor in AD pathogenesis. Immunotherapy targeting Aβ for preventing aggregation of Aβ and mildly clearing amyloid plaques has been a hot topic since 1999. Although the first clinical trial of Aβ vaccine, AN-1792, failed in phase II, its results suggested some key points in the design of Aβ vaccines. Avoiding the possible toxic Aβ specific T cell response and inducing a Th2 type cellular immune response may be beneficial for Aβ immunotherapy. Many associations and research groups are working on Aβ vaccine and some progress has been made in recent years. In this review, we have provided a detailed summary of past Aβ vaccines, which have been sorted by the immunogen, and we also discuss some recent progress and future perspectives.     

Molecular path for ligand search

A ligand is a small molecule bind to several residues of a receptor.We adapt the concept of molecular path for effective ligand search with its contacting residues.Additionally,we allow wild type definitions on atoms and bonds of molecular paths for fuzzy algorithms on structural match.We choose hydrogen bond interactions to characterize the binding mode of a ligand by several proper molecular paths and use them to query the deposited ligands in PDBe that interact with their residues in the same way. Expression of molecular path and format of database entries are described with examples.Our molecular path provides a new approach to explore the ligand-receptor interactions and to provide structural framework reference on new ligand design.     

A membrane separation technique for optimizing sample preparation of MALDI-TOF MS detection

Here, we report a new method based on the combination of membrane separation technology and nanomaterial to rapid detection of peptides and protein with MALDI-TOF MS. This method shows advantages as it can inhibit the heterogeneous of sample spot and enhance the target molecular signal intensity.     

Programmed co-assembly of DNA-peptide hybrid microdroplets by phase separation

Biopolymers, including DNA and peptides have been used as excellent self-assembling building blocks for programmable single-component or hybrid materials, due to their controlled molecular interactions.However, combining two assembling principles of DNA-based programmability and peptide-based specific molecular interactions for hybrid structures to microscale has not yet been achieved. In this study,we describe a hybrid microsystem that emerges from the co-assembly of DNA origami structure and s...     

Isolated supramolecules on surfaces studied with scanning tunneling microscopy

To date, supramolecular chemistry is an ever growing research field owing to its crucial role in molecular catalysis, recognition, medicine, data storage and processing as well as artificial photosynthetic devices.Different isolated supramolecules were prepared by molecular self-assembly on surfaces. This review mainly focuses on supramolecular aggregations on noble metal surfaces studied by scanning tunneling microscopy, including dimers, trimers, tetramers, pentamers, wire-like assemblies and Sierpin′ ski triangular fractals. The variety of self-assembled structures reflects the subtle balance between intermolecular and molecule–substrate interactions, which to some extent may be controlled by molecules, substrates and the molecular coverage. The comparative study of different architectures helps identifying the operative mechanisms that lead to the structural motifs. The application of these mechanisms may lead to novel assemblies with tailored physicochemical properties.     

AFM and fluorescence spectrascopy investigation for disaggregation of existing Aβ fibrils by baicalein

The wavelength for the peak of fluorescence emission of thioflavin T（ThT） was changed from 445 nm to 481 nm when ThT was added in Aβ solution which indicating theβ-sheet structure of Aβ fibril.The significant decrease in the intensity of fluorescence at 481 nm was observed when the baicalein was added in mixed solution of Aβ and ThT,suggesting that the depolymerization of Aβ fibrils happened and there were Aβfibrils left to react with ThT to keep the initial fluorescence intensity.And the existing Aβfibrils are disaggregated by baicalein in a time- and dose-dependent manner.AFM images of the morphologies of the Aβ_1-42 fibrils obviously changed smaller and more dispersive when baicalein added indicating also the depolymerization of Aβ.The results demonstrate a basis for development of a potential herb drug candidate for the treatment of Alzheimer’s disease（AD）.     

Molecular dynamics studies of the inhibitory mechanism of copper（Ⅱ） on aggregation of amyloid β-peptide

The inhibitory mechanism of copper（Ⅱ） on the aggegation of amyloid β-peptide （Aβ） was investigated by molecular dynamics simulations. The binding mode ofcopper（Ⅱ） with Aβ is characterized by the imidazole nitrogen atom, Nπ, of the histidine residue H 13, acting as the anchoring site, and the backbone＇s deprotoned amide nitogen atoms as the main binding sites. Drove by the coordination bonds and their induced hydrogen bond net, the conformations of Aβ converted from β-sheet non-β-sheet conformations, which destabilized the aggregation of Aβ into fibrils.     

How do molecular interactions affect fluorescence behavior of AIEgens in solution and aggregate states?

Molecular interactions are crucial in diverse fields of protein folding,material science,nanotechnology,and life origins.Although mounting experimental research controls luminescent behavior by adjusting molecular interactions in light-emitting materials,it remains elusive to correlate microscopic molecular interactions with macroscopic luminescent behavior directly.Here,we synthesized three red luminogens with subtle structural variation and investigated the influence of molecular interactions on their luminescent behavior in solution and aggregate states.Our results indicate that strongπ-πand D-A interactions in both dilute solution(between luminogen and solvent molecules)and aggregate(between luminogens)states cause the redshift in emission,while weak interactions(e.g.,Van der Waals,C–H…π,and C–H…F interactions)enhance the quantum yield.This work provides a thoughtful investigation into the complicated influence of various molecular interactions on luminescent behavior.     

3D-QSAR and docking studies of estrogen compounds based on estrogen receptor β

Close attention has been paid to estrogen compounds because these chemicals may pose a serious threat to the health of humans and wildlife. Estrogen receptor (ER) exists as two subtypes, ERα and ERβ. The difference in amino acids sequence of the binding sites of ERα and ERβ might lead to a result that some synthetic estrogens and naturally occurring steroidal ligands have different relative affinities and binding modes for ERα and ERβ. In this investigation, comparative molecular similarity indices analysis...