Inhibition Of Aβ Aggregation Research Articles

Fluorescence Detection and Dissociation of Amyloid‐β Species for the Treatment of Alzheimer's Disease

AbstractAlzheimer's disease (AD) is one of the most prevalent forms of neurodegenerative disease. It is well established that the β‐amyloid peptide (Aβ) species existing in several forms, such as soluble monomers, oligomers, and insoluble aggregates, play an essential role in the pathophysiology of AD. Therefore, much effort has been made to specifically detect Aβ species and to inhibit Aβ aggregation for the treatment of AD. In this review, an overview of recent advances in detecting different Aβ forms mainly containing Aβ aggregates, Aβ oligomers, and Aβ protofibrils is provided. In addition, photodynamic therapy (PDT) and photothermal therapy (PTT) are considered to be promising modalities for the treatment of AD because of the minimal invasiveness and high spatial selectivity. Herein, the strategies of inhibiting Aβ aggregation and dissociating Aβ aggregates using PDT, PTT, and Aβ inhibitors for the treatment of AD are summarized.

Design and Synthesis of 2-Substitutedphenyl Benzo[D]Thiazole Derivatives and Their β-Amyloid Aggregation and Cholinesterase Inhibitory Activities

The occurrence of amyloid-β (Aβ) and reduced cholinergic tranmission are two major hallmarks of Alzheimer’s disease (AD). Therefore, a series of new 2-phenylbenzo[d]thiazoles substituted with azole/piperazine moieties were designed, synthesized, and evaluated as potential dual inhibitors of Aβ aggregation and cholinesterase (ChE) activities. In vitro studies showed that compound 2m containing an imidazole ring strongly inhibited Aβ1–40 (49.2%) and Aβ1-42 aggregation (60.6%). All derivatives exhibited weak inhibitory activities against both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Therefore, compound 2m may represent promising therapeutic option for inhibiting Aβ-mediated pathology in AD.

P2‐217: SUPRATHERAPEUTIC CONCENTRATIONS OF CILOSTAZOL INHIBITS β‐AMYLOID OLIGOMERIZATION IN VITRO

Alzheimer disease (AD) is the most common type of dementia, and is currently incurable. The efficacy of existing treatments for AD such as acetylcholinesterase inhibitors is limited to symptom improvement. Research on disease-modifying therapies (DMTs) has conventionally focused on amelioration of CNS pathogenesis. Two neuropathological changes correlate strongly with AD, the appearance of neurofibrillary tangles containing the microtubule-associated protein tau and extracellular amyloid deposits containing amyloid β-protein (Aβ). The aggregation of Aβ is believed to be the key pathogenic event in AD, with oligomeric assemblies thought to be the most neurotoxic form. Inhibitors of oligomer formation, therefore, could be valuable therapeutics for AD patients. The clinical phosphodiesterase type-3 inhibitor cilostazol (CSZ) was recently found to suppress the progression of cognitive decline in patients with stable AD receiving acetylcholinesterase inhibitors. We examined the effects of CSZ on in vitro aggregations of Aβ1-40 and Aβ1-42 including oligomerization, using the thioflavin T assay, photo-induced cross-linking of unmodified proteins, and electron microscopy. CSZ (25-100 μM) inhibited Aβ aggregation, especially oligomer formation. Considering that CSZ might be a key molecule for DMTs of AD, it cannot be ruled out that the low concentration of CSZ achievable in patient dosing may display some ant-oligomeric activity in synergy with its known therapeutic effects.

Rosmarinic acid suppresses Alzheimer\u2019s disease development by reducing amyloid \u03b2 aggregation by increasing monoamine secretion

A new mechanism is revealed by which a polyphenol, rosmarinic acid (RA), suppresses amyloid β (Aβ) accumulation in mice. Here we examined the brains of mice (Alzheimer’s disease model) using DNA microarray analysis and revealed that the dopamine (DA)-signaling pathway was enhanced in the group fed RA versus controls. In the cerebral cortex, the levels of monoamines, such as norepinephrine, 3,4-dihydroxyphenylacetic acid, DA, and levodopa, increased after RA feeding. The expression of DA-degrading enzymes, such as monoamine oxidase B (Maob), was significantly downregulated in the substantia nigra and ventral tegmental area, both DA synthesis regions. Following in vitro studies showing that monoamines inhibited Aβ aggregation, this in vivo study, in which RA intake increased concentration of monoamine by reducing Maob gene expression, builds on that knowledge by demonstrating that monoamines suppress Aβ aggregation. In conclusion, RA-initiated monoamine increase in the brain may beneficially act against AD.

Glycopeptide Nanofiber Platform for Aβ-Sialic Acid Interaction Analysis and Highly Sensitive Detection of Aβ.

The variation of amyloid β peptide (Aβ) concentration and Aβ aggregation are closely associated with the etiology of Alzheimer's diseases (AD). The interaction of Aβ with the monosialoganglioside-rich neuronal cell membrane has been suggested to influence Aβ aggregation. Therefore, studies on the mechanism of Aβ and sialic acids (SA) interaction would greatly contribute to better understanding the pathogenesis of AD. Herein, we report a novel approach for Aβ-SA interaction analysis and highly sensitive Aβ detection by mimicing the cell surface presentation of SA clusters through engineering of SA-modified peptide nanofiber (SANF). The SANF displayed well-ordered 1D nanostructure with high density of SA on surface. Using FAM-labeled Aβ fragments of Aβ1-16, Aβ16-23, and Aβ24-40, the interaction between Aβ and SA was evaluated by the fluorescence titration experiments. It was found that the order of the SA-binding affinity was Aβ1-16 > Aβ24-40 > Aβ16-23. Importantly, the presence of full-length Aβ1-40 monomer triggered a significant fluorescence enhancement due to the multivalent binding of Aβ1-40 to the nanofiber. This fluorescent turn-on response showed high selectivity and sensitivity for Aβ1-40 detection and the method was further used for Aβ aggregation process monitoring and inhibitor screening. The results suggest the proposed strategy is promising to serve as a tool for mechanism study and the early diagnosis of Alzheimer's disease.

Design, synthesis, in-silico and biological evaluation of novel chalcone-O-carbamate derivatives as multifunctional agents for the treatment of Alzheimer's disease

To discover multifunctional agents for the treatment of Alzheimer's disease (AD), a series of chalcone-O-carbamate derivatives was designed and synthesized based on the multitarget-directed ligands strategy. The in vitro biological activities were evaluated including AChE/BChE inhibition, MAO-A/MAO-B inhibition, antioxidant activities, Aβ1-42 aggregation inhibition, metal-chelating properties and neuroprotective effects against H2O2-induced PC12 cell injury. The results showed compounds 5b and 5h indicated highly selective BChE inhibitory activity with IC50 values of 3.1 μM and 1.2 μM, respectively and showed highly selective MAO-B inhibitory potency with IC50 values of 1.3 μM and 3.7 μM, respectively. In addition, compounds 5b and 5h could inhibit self-induced Aβ1-42 aggregation with 63.9% and 53.1% inhibition percent rate, respectively. Particularly, compound 5b was a potent antioxidant agent and neuroprotectant, as well as a selective metal chelator by chelating Cu2+ and Al3+. Moreover, compound 5b could inhibit and disaggregate Cu2+-induced Aβ1-42 aggregation, which was further supported by the TEM images. Furthermore, compounds 5b and 5h could cross the blood-brain barrier (BBB) in vitro and conformed to the Lipinski's rule of five. Finally, the in vivo assay exhibited that compound 5b could improve scopolamine-induced cognitive impairment. Taken together, these results revealed that compound 5b might be a potential multifunctional agent for the treatment of AD, and deserved to do further structure optimization.

Development of the “hidden” multifunctional agents for Alzheimer's disease

Alzheimer's disease (AD) is a chronic, fatal and complex neurodegenerative disorder, which is characterized by cholinergic system dysregulation, metal dyshomeostasis, amyloid-β (Aβ) aggregation, etc. Therefore in most cases, single-target or single-functional agents are insufficient to achieve the desirable effect against AD. Multi-Target-Directed Ligand (MTDL), which is rationally designed to simultaneously hit multiple targets to improve the pharmacological profiles, has been developed as a promising approach for drug discovery against AD. To identify the multifunctional agents for AD, we developed an innovative method to successfully conceal the metal chelator into acetylcholinesterase (AChE) inhibitor. Briefly, the “hidden” agents first cross the Blood Brain Barrier (BBB) to inhibit the function of AChE, and the metal chelator will then be released via the enzymatic hydrolysis by AChE. Therefore, the AChE inhibitor, in this case, is not only a single-target agent against AD, but also a carrier of the metal chelator. In this study a total of 14 quinoline derivatives were synthesized and biologically evaluated. Both in vitro and in vivo results demonstrated that compound 9b could cross the BBB efficiently, then release 8a, the metabolite of 9b, into brain. In vitro, 9b had a potent AChE inhibitory activity, while 8a displayed a significant metal ion chelating function, therefore in combination, both 9b and 8a exhibited a considerable inhibition of Aβ aggregation, one of the observations that plays important roles in the pathogenesis of AD. The efficacy of 9b against AD was further investigated in both a zebrafish model and two different mice models.

Peptide‐Modified Mo Polyoxometalate Nanoparticles Suppress Zn2+‐Induced Aβ Aggregation

AbstractThe abnormal metabolism of amyloid‐β (Aβ) peptide, as one of the main components of senile plaques, plays a vital role in the pathogenesis of Alzheimer's disease (AD). Our previous work showed that polyoxometalates (POMs) that inhibited the formation of Aβ aggregates were promising for AD therapy. Here, peptide‐modified Mo polyoxometalate (Mo‐POMs) nanoparticles were synthesized by the self‐assembly of Aβ target peptide and Mo‐POMs based on our previous work. Importantly, after modifying with the Aβ target peptide, the Mo polyoxometalate (Mo‐POMs) nanoparticles exhibited enhanced blood‐brain barrier (BBB) penetration and high binding affinity with Aβ species. The interactions between the Peptide@Mo‐POMs nanoparticle and Aβ in the presence of Zn2+ were comprehensively studied using physicochemical methods (spectroscopy, ThT fluorescence, turbidity tests). Peptide@Mo‐POMs could suppress Aβ aggregation, disaggregate Aβ fibrils, and suppress Zn2+‐induced Aβ aggregation. In addition, in vitro cell experiments revealed that Peptide@Mo‐POMs could target and be well absorbed by PC12 cells, leading to the inhibition of intracellular Aβ aggregation and reduced Aβ aggregates‐induced cytotoxicity. The blood‐brain barrier (BBB) permeability of Peptide@Mo‐POMs was also revealed by the Transwell experiment. This study gives a mechanistic understanding into how Peptide@Mo‐POMs can work through a synergistic interaction with metal ions and Aβ, and provides new insights into the design and synthesis of POMs as Aβ inhibitors in the treatment of AD.

Therapeutic Strategies Targeting Amyloid-β in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder linked to protein misfolding and aggregation. AD is pathologically characterized by senile plaques formed by extracellular Amyloid-β (Aβ) peptide and Intracellular Neurofibrillary Tangles (NFT) formed by hyperphosphorylated tau protein. Extensive synaptic loss and neuronal degeneration are responsible for memory impairment, cognitive decline and behavioral dysfunctions typical of AD. Amyloidosis has been implicated in the depression of acetylcholine synthesis and release, overactivation of N-methyl-D-aspartate (NMDA) receptors and increased intracellular calcium levels that result in excitotoxic neuronal degeneration. Current drugs used in AD treatment are either cholinesterase inhibitors or NMDA receptor antagonists; however, they provide only symptomatic relief and do not alter the progression of the disease. Aβ is the product of Amyloid Precursor Protein (APP) processing after successive cleavage by β- and γ-secretases while APP proteolysis by α-secretase results in non-amyloidogenic products. According to the amyloid cascade hypothesis, Aβ dyshomeostasis results in the accumulation and aggregation of Aβ into soluble oligomers and insoluble fibrils. The former are synaptotoxic and can induce tau hyperphosphorylation while the latter deposit in senile plaques and elicit proinflammatory responses, contributing to oxidative stress, neuronal degeneration and neuroinflammation. Aβ-protein-targeted therapeutic strategies are thus a promising disease-modifying approach for the treatment and prevention of AD. This review summarizes recent findings on Aβ-protein targeted AD drugs, including β-secretase inhibitors, γ-secretase inhibitors and modulators, α-secretase activators, direct inhibitors of Aβ aggregation and immunotherapy targeting Aβ, focusing mainly on those currently under clinical trials.

Naturally occurring biflavonoids with amyloid β aggregation inhibitory activity for development of anti-Alzheimer agents

Amyloid β (Aβ) aggregation plays an essential role in promoting the progression of Alzheimer's disease (AD). Therefore, the inhibition of Aβ aggregation is a potential therapeutic approach for AD. Herein, twenty-seven biflavonoids with different inter-flavonyl linkages and methoxy substitution patterns were isolated from several plants, and their Aβ40 aggregation inhibitory activity was evaluated by the thioflavin-T fluorescence assay. Amentoflavone (1) and its monomethoxy derivatives (2, 3, and 5) exhibited the most potent inhibitory activity, with IC50 values of approximately 5 μM. It was clarified that increasing the number of methoxy substituents on the biflavonoid structures attenuated the inhibitory activity. Moreover, the linkage and the methoxy substitution pattern had a marked influence on the inhibitory activity. Our investigation strongly supports that biflavonoids can be considered a new type of anti-Alzheimer agents that may be successfully developed for AD patients.

Exploring Amyloid-β Dimer Structure Using Molecular Dynamics Simulations.

A major hallmark of Alzheimer's disease (AD) is the aggregation of amyloid-β peptides in the brains of people afflicted by the disease. The exact pathway to this catastrophic event is unknown. In this work, a total of 9.5 μs molecular dynamics simulations have been performed to investigate the structure and dynamics of the smallest form of toxic Aβ oligomers, i.e., the Aβ dimers. This study suggests that specific hydrophobic regions are vital in the aggregation process. Different possible structures for Aβ dimers are reported along with their relative binding affinity. These data may be used to design better Aβ-aggregation inhibitors. The diversity of the dimer structures suggests several aggregation pathways.

Potent Acetylcholinesterase Selective and Reversible Homodimeric Agent Based on Tacrine for Theranostics.

Acetylcholinesterase (AChE) has been an important biomarker for diagnosing Alzheimer's disease (AD), due to reduction in AChE activity in post-mortem brains of AD patients. A potent, selective, and reversible homodimeric inhibitor of AChE, 5-amino- N1, N3-bis(2-(1,2,3,4-tetrahydroacridin-9-ylamino)ethyl)isophthalamide (compound 4), was synthesized by using 9-alkyl(1,2,3,4-tetrahydroacridine) pharmacophore with appended functionality. In the present work, we report the synthesis of this bivalent inhibitor of AChE. The homodimeric ligand structure was designed and studied with molecular docking tools, which revealed its high affinity and interactions with active site gorge of AChE, which includes both catalytic active site (CAS) and peripheral active site (PAS). The IC50 value of this bivalent inhibitor for AChE and BuChE were 0.54 ± 0.06 and 32.49 ± 1.2 nM, respectively, with a selectivity ratio of 60.16 toward AChE. The designed ligand also showed potent inhibitory properties on PAS activity as well as on AChE-induced amyloid aggregation with low cytotoxicity on rat hippocampal neurons. The AFM images further corroborated the Aβ1-42 aggregation inhibition by compound 4 to an extent similar to bis(7)-tacrine. Moreover, the bivalent ligand was also proven to be of neurogenic potential due to its ability to induce S-phase post-treatment in rat hippocampal neuronal cells. On the basis of initial results, the agent could be further explored for its theranostic value clinically, which gives the possibility of tracing the AChE levels by molecular imaging techniques in correlation with progression of neurocognitive disorders like AD for better therapy response and patient management.

A multifunctional therapeutic approach: Synthesis, biological evaluation, crystal structure and molecular docking of diversified 1H-pyrazolo[3,4-b]pyridine derivatives against Alzheimer's disease

2-(piperazin-1-yl)N-(1H-pyrazolo[3,4-b]pyridin-3-yl)acetamides are described as a new class of selective and potent acetylcholinesterase (AChE) inhibitors and amyloid β aggregation inhibitors. Formation of synthesized compounds (P1P9) was justified via H1 NMR, C13 NMR, mass spectra and single crystal X-Ray diffraction study. All compounds were evaluated for their acetylcholinesterase and butyrylcholinesterase inhibitory activity, inhibition of self-mediated Aβ aggregation and Cu(II)-mediated Aβ aggregation. Also, docking study carried out was in concordance with in vitro results. The most potent molecule amongst the derivatives exhibited excellent anti-AChE activity (IC50 = 4.8 nM). Kinetic study of P3 suggested it to be a mixed type inhibitor. In vitro study revealed that all the compounds are capable of inhibiting self-induced β-amyloid (Aβ) aggregation with the highest inhibition percentage to be 81.65%. Potency of P1 and P3 to inhibit self-induced Aβ1-42 aggregation was ascertained by TEM analysis. Compounds were also evaluated for their Aβ disaggregation, antioxidation, metal-chelation activity.

LVFFARK conjugation to poly (carboxybetaine methacrylate) remarkably enhances its inhibitory potency on amyloid β-protein fibrillogenesis

Fibrillar aggregation of amyloid β-protein (Aβ) is complicated in the pathological process of Alzheimer's disease (AD). Therefore, inhibition of Aβ aggregation is considered as a promising strategy for the precaution and treatment of AD. Ac-LVFFARK-NH2 (LK7) has been recognized as an inhibitor of Aβ aggregation, but its propensity to aggregation and strong cytotoxicity limited its applications. Thus, we have herein conjugated LK7 to a zwitterionic polymer, poly (carboxybetaine methacrylate) (pCB), and synthesized three LK7@pCB conjugates of different degrees of substitution (DS). The conjugation eliminated the aggregation propensity of LK7 and the conjugates self-assembled into micelles. It revealed that the LK7@pCB micelles inhibited Aβ fibrillogenesis and mitigated the amyloid cytotoxicity more efficiently than free LK7. Structural analysis indicated that LK7@pCB micelles suppressed the conformational transition of Aβ42 into β-sheet structure and thus changed its aggregation pathway. The superiority of LK7@pCB is considered due to the integrated functions of LK7 and pCB. Namely, high local LK7 concentration in the micellar interior significantly enhanced the interactions between Aβ42 and LK7, and the dense hydration layer on pCB strongly stabilized the bound Aβ on LK7 anchored on pCB, restricted its conformational transition and the following on-pathway fibrillation.

WS-5 Extract of Curcuma longa, Chaenomeles sinensis, and Zingiber officinale Contains Anti-AChE Compounds and Improves β-Amyloid-Induced Memory Impairment in Mice.

Alzheimer's disease (AD) is linked to an extensive neuron loss via accumulation of amyloid-beta (Aβ) as senile plaques associated with reactive astrocytes and microglial activation in the brain. The objective of this study was to assess the therapeutic effect of WS-5 ethanol extract in vitro and in vivo against Aβ-induced AD in mice and to identify the extract's active constituents. In the present study, WS-5 exerted a significant inhibitory effect on acetylcholinesterase (AChE). Analysis by transmission electron microscopy (TEM) revealed that WS-5 prevented Aβ oligomerization via inhibition of Aβ1-42 aggregation. Evaluation of antioxidant activities using 1, 1-diphenyl-2-picrylhydrazyl (DPPH) demonstrated that WS-5 possessed a high antioxidant activity, which was confirmed by measuring the total antioxidant status (TAS). Furthermore, the anti-inflammatory properties of WS-5 were examined using lipopolysaccharide-stimulated BV-2 microglial cells. WS-5 significantly inhibited the lipopolysaccharide–induced production of nitric oxide and two proinflammatory cytokines, TNF-α and IL-6. The memory impairment in mice with Aβ-induced AD was studied using the Morris water maze and passive avoidance test. Immunohistochemistry was performed to monitor pathological changes in the hippocampus and cortex region of the mouse brain. The animal study showed that WS-5 (250 mg/kg) treatment improved learning and suppressed memory impairment as well as reduced Aβ plaque accumulation in Aβ-induced AD. HPLC analysis identified the extract's active compounds that exert anti-AChE activity. In summary, our findings suggest that WS-5 could be applied as a natural product therapy with a focus on neuroinflammation-related neurodegenerative disorders.

Protein Disulfide Isomerase Disrupts and Detoxifies Aggregates of Amyloid Beta Peptide

Aggregated fibrils of amyloid beta (Aβ) peptide induce the neurotoxicity characteristic of Alzheimer's Disease. The inhibition of Aβ aggregation could therefore represent a therapeutic target for Alzheimer's Disease. Protein disulfide isomerase (PDI) is an oxidoreductase and chaperone that has been shown to effectively inhibit the formation of Aβ fibrils when present at the onset of aggregation. However, the potential disruption of ongoing Aβ fibrillization by PDI has not been demonstrated. We examined the disruptive effect of PDI on Aβ aggregation using a Thioflavin‐T fluorescence assay to monitor Aβ fibrillization. PDI prevented the aggregation of monomeric Aβ at a sub‐stoichiometric 1:10 molar ratio of PDI:Aβ. Fibrillization was partially inhibited by a 1:50 molar ratio of PDI:Aβ and was not affected by a 1:100 molar ratio of PDI:Aβ. As such, a 1:10 molar ratio of PDI:Aβ was used for all subsequent experiments. We next found that PDI could also disrupt Aβ fibrillization when added 2, 4, or 10 h after the initiation of aggregation. Cell culture studies using an MTS cell viability assay further demonstrated that PDI can protect neuronal cells from extracellular aggregates of Aβ when added 2 h after the initiation of aggregation. These findings demonstrate PDI is able to disrupt Aβ aggregation at sub‐stoichiometric molar ratios and support the potential use of PDI as a novel therapy for Alzheimer's Disease.Support or Funding InformationFlorida Department of Health, Ed and Ethel Moore Alzheimer's Disease Research Program Grant 8AZ12This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Coumarin derivatives as acetyl- and butyrylcholinestrase inhibitors: An in vitro, molecular docking, and molecular dynamics simulations study

Alzheimer's disease is an irreversible and progressive brain disease that can cause problems with memory and thinking skills. It is characterized by loss of cognitive ability and severe behavioral abnormalities, and could lead to death. Cholinesterases (ChEs) play a crucial role in the control of cholinergic transmission, and subsequently, the acetylcholine level in the brain is upgraded by inhibition of ChEs. Coumarins have been shown to display potential cholinesterase inhibitory action, where the aromatic moiety has led to the design of new candidates that could inhibit Aβ aggregation. Accordingly, the present work is an in vitro activity, along with docking and molecular dynamics (MD) simulation studies of synthesized coumarin derivatives, to explore the plausible binding mode of these compounds inside the cholinesterase enzymes. For this purpose, a series of previously prepared N1-(coumarin-7-yl) derivatives were screened in vitro for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities. The assayed compounds exhibited moderate inhibitory activity against AChE, with IC50 values ranging from 42.5 ± 2.68 to 442 ± 3.30 μM. On the other hand, the studied compounds showed remarkable activity against BChE with IC50 values ranging from 2.0 ± 1.4 nM to 442 ± 3.30 μM. In order to better understand the ligand binding site interaction of compounds and the stability of protein-ligand complexes, a molecular docking with molecular dynamics simulation of 5000 ps in an explicit solvent system was carried out for both cholinesterases. We concluded that the tested coumarin derivatives are potential candidates as leads for potent and efficacious ChEs inhibitors.

Polyphenols Modulate Alzheimer's Amyloid Beta Aggregation in a Structure-Dependent Manner.

Some polyphenols, which are common natural compounds in fruits, vegetables, seeds, and oils, have been considered as potent inhibitors of amyloid beta (Aβ) aggregation, one critical pathogenic event in Alzheimer’s disease (AD). However, the mechanisms by which polyphenols affect aggregation are not fully understood. In this study, we aimed to investigate the effect of two classes of polyphenols (flavonoids and stilbenes) on the self-assembly of Aβ_42, in particular, how this relates to structure. We found that the flavonoids gallocatechin gallate (GCG) and theaflavin (TF) could completely inhibit Aβ aggregation, while two stilbenes, resveratrol and its glucoside derivative piceid, could also suppress Aβ aggregation, but to a much lesser extent. Intriguingly, resveratrol accelerated the formation of Aβ fibrils before its decreasing effect on fibrillation was detected. Atomic force microscopy (AFM) images showed a huge mass of long and thin Aβ fibrils formed in the presence of resveratrol. Although the morphology was the same in the presence of piceid, the fibrils were sparse in the presence of picead. In the presence of flavonoids, Aβ morphology was unchanged from prior to incubation (0 h), in agreement with amyloid beta kinetics analysis using thioflavin-T fluorescence assay. The electrochemical data showed a higher ability of GCG and TF to interact with Aβ than resveratrol and piceid, which could be attributed to the presence of more aromatic rings and hydroxyl groups. In addition, the two flavonoids exhibited a similar propensity for Aβ aggregation, despite having some differences in their structure. However, in the case of stilbenes, the addition of a glucoside at C-7 slightly decreased anti-Aβ aggregation property compared to resveratrol. These findings contribute to a better understanding of the essential structural features of polyphenols required for inhibiting Aβ aggregation, and the possible mechanisms for modulating aggregation.

Extending Lifespan of Alzheimer’s Mode Nematode CL4176 Using a Novel Bifunctional Peptide with Inhibition of β-Amyloid Aggregation and Anti-oxidation

Alzheimer’s disease(AD) is a neurodegenerative disorder characterized by the deposition of β-amyloid peptide(Aβ) in the brain tissues, and an imbalance in the oxidant-antioxidant system. Compounds with antioxidant activity and the ability to inhibit Aβ aggregation therefore potentially treat AD. In this study, we designed an iron-porphyrin containing bifunctional peptide(BP, Deuterohemin-AlaHisThrValGluLysLeuProPhePheAsp) based on natural microperoxidase-11(MP-11) and typical β-sheet breaker LPFFD(iAβ5p). This BP substantially reduced the aggregation of Aβ and caused oligomer disassembly, by binding Aβ with affinity constant of 9.07 μmol/L. Furthermore, it showed a neuroprotective effect on Aβ25—35 induced toxicity in SH-SY5Y cells, and significantly alleviated Aβ-induced paralysis and extended lifespan in Aβ1—42 transgenic C. elegans(CL4176). It also showed a potent peroxidase activity of 20.8 U/mg, and scavenged free radicals both in vitro and in vivo. In addition, BP up-regulated the levels of hsp16.2, hsp16.41, and hsp12.6 mRNAs to 183.26%, 160.16%, and 162.64% respectively, and down-regulated that of hsp70 to 36.76% in C. elegans. Taken together, the synthetic BP inhibited Aβ aggregation and showed antioxidant activity, indicating the therapeutic potential of novel peptide drugs against AD.

Chiral resolution and bioactivity of enantiomeric furofuran lignans from Juglans mandshurica Maxim

Enantiomers have generally been reported mostly for racemic mixtures with a 1:1 ratio, as in that case there were weak Cotton effects in the ECD spectrum and negligible optical rotations. A furofuran lignan (sesamin), with a remarkable rotation and significant Cotton effects, was isolated from Juglans mandshurica Maxim. Subsequently, sesamin was resolved by chiral HPLC to afford a pair of enantiomers, (+)-sesamin (a) and (−)-sesamin (b), in a ratio of approximately 1:3. Their absolute configurations were determined by computational analysis of their electronic circular dichroism (ECD) spectrum. In addition, the pair of enantiomers were evaluated for the inhibition of self-induced Aβ aggregation. Interestingly, (+)-sesamin (a) (67.7%) and (−)-sesamin (b) (80.6%) exhibited different degrees of anti-Aβ aggregation activity. The different inhibition profiles were further explained by molecular dynamics and docking simulation study.