Aβ Inhibition Research Articles

Abstract LB052: Melanoma-secreted amyloid beta suppresses neuroinflammation and promotes brain metastasis

Abstract Brain metastasis is a significant cause of morbidity and mortality in multiple cancer types and represents an unmet clinical need. The mechanisms that mediate metastatic cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the highest rate of brain metastasis among common cancer types, is an ideal model to study how cancer cells adapt to the brain parenchyma. Our unbiased proteomics analysis of melanoma short-term cultures revealed that proteins implicated in neurodegenerative pathologies are differentially expressed in melanoma cells explanted from brain metastases compared to those derived from extracranial metastases. We showed that melanoma cells require amyloid beta (Aβ) for growth and survival in the brain parenchyma. Melanoma-secreted Aβ activates surrounding astrocytes to a prometastatic, anti-inflammatory phenotype and prevents phagocytosis of melanoma by microglia. Finally, we demonstrate that pharmacological inhibition of Aβ decreases brain metastatic burden. Our results reveal a novel mechanistic connection between brain metastasis and Alzheimer’s disease - two previously unrelated pathologies, establish Aβ as a promising therapeutic target for brain metastasis, and demonstrate suppression of neuroinflammation as a critical feature of metastatic adaptation to the brain parenchyma. Citation Format: Kevin Kleffman, Grace Levinson, Indigo V. Rose, Lili Blumenberg, Sorin A. Shadaloey, Avantika Dhabaria, Eitan Wong, Francisco Galán-Echevarría, Alcida Karz, Diana Argibay, Richard Von-Itter, Alfredo Floristán, Gillian Baptiste, Nicole Eskow, James Tranos, Jenny Chen, Eleazar C. Vega Saenz de Miera, Melissa Call, Robert Rogers, George Jour, Youssef Zaim Wadghiri, Iman Osman, Yue Ming Li, Paul Mathews, Ronald Demattos, Beatrix Ueberheide, Kelly Ruggles, Shane A. Liddelow, Robert J. Schneider, Eva Hernando. Melanoma-secreted amyloid beta suppresses neuroinflammation and promotes brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB052.

Cross-seeding between Aβ and SEVI indicates a pathogenic link and gender difference between alzheimer diseases and AIDS.

Amyloid-β (Aβ) and semen-derived enhancer of viral infection (SEVI) are considered as the two causative proteins for central pathogenic cause of Alzheimer’s disease (AD) and HIV/AIDS, respectively. Separately, Aβ-AD and SEVI-HIV/AIDS systems have been studied extensively both in fundamental research and in clinical trials. Despite significant differences between Aβ-AD and SEVI-HIV/AIDS systems, they share some commonalities on amyloid and antimicrobial characteristics between Aβ and SEVI, there are apparent overlaps in dysfunctional neurological symptoms between AD and HIV/AIDS. Few studies have reported a potential pathological link between Aβ-AD and SEVI-HIV/AIDS at a protein level. Here, we demonstrate the cross-seeding interactions between Aβ and SEVI proteins using in vitro and in vivo approaches. Cross-seeding of SEVI with Aβ enabled to completely prevent Aβ aggregation at sub-stoichiometric concentrations, disaggregate preformed Aβ fibrils, reduce Aβ-induced cell toxicity, and attenuate Aβ-accumulated paralysis in transgenic AD C. elegans. This work describes a potential crosstalk between AD and HIV/AIDS via the cross-seeding between Aβ and SEVI, identifies SEVI as Aβ inhibitor for possible treatment or prevention of AD, and explains the role of SEVI in the gender difference in AD.

Inhibition of Aβ16-22 Peptide Aggregation by Small Molecules and Their Permeation through POPC Lipid Bilayer: Insight from Molecular Dynamics Simulation Study.

Alzheimer's Disease is a rapidly progressing irreversible neurodegenerative disorder characterized by neuronal cell deterioration that endangers human health. With its proper therapeutic treatment being unavailable, several research groups throughout the world are involved in designing efficient drug molecules. However, the elusive mechanism of action of the drugs as well as their debilitating side effects pose major challenges in this regard. In the present article, we investigated the inhibitory effect of an indanone-carbamate-based molecule on Aβ16-22 peptide aggregation by employing a series of all-atom molecular dynamics simulation study. To gain explicit insights, we studied the role of inhibitor molecules on the disruption of highly arranged β-sheet of peptides by various types of analyses such as structural analysis, Cα-Cα-atom distance, residue-wise contact map, and solvent accessible surface area. The results obtained from various analyses revealed that the inhibitor molecules interacted with Aβ16-22 peptides to destabilize its arranged β-sheet conformer via hydrophobic interaction. To further comprehend the effect of inhibitors on amyloid aggregation, we also determined interaction energy, hydration number, radial distribution function, hydrogen bonding, and potential of mean forces. In addition, the permeability of the inhibitors through model POPC lipid bilayer via passive diffusion was also analyzed. Our study is noteworthy in that it elucidates the strong interaction between inhibitors and the central hydrophobic core of peptides comprising aromatic phenylalanine residues, as well as the passive translocation of inhibitors across POPC lipid bilayers.

Linking Alzheimer's Disease and Type 2 Diabetes: Characterization and Inhibition of Cytotoxic Aβ and IAPP Hetero-Aggregates.

The cytotoxic self-aggregation of β-amyloid (Aβ) peptide and islet amyloid polypeptide (IAPP) is implicated in the pathogenesis of Alzheimer’s disease (AD) and Type 2 diabetes (T2D), respectively. Increasing evidence, particularly the co-deposition of Aβ and IAPP in both brain and pancreatic tissues, suggests that Aβ and IAPP cross-interaction may be responsible for a pathological link between AD and T2D. Here, we examined the nature of IAPP-Aβ40 co-aggregation and its inhibition by small molecules. In specific, we characterized the kinetic profiles, morphologies, secondary structures and toxicities of IAPP-Aβ40 hetero-assemblies and compared them to those formed by their homo-assemblies. We demonstrated that monomeric IAPP and Aβ40 form stable hetero-dimers and hetero-assemblies that further aggregate into β-sheet-rich hetero-aggregates that are toxic (cell viability <50%) to both PC-12 cells, a neuronal cell model, and RIN-m5F cells, a pancreatic cell model for β-cells. We then selected polyphenolic candidates to inhibit IAPP or Aβ40 self-aggregation and examined the inhibitory effect of the most potent candidate on IAPP-Aβ40 co-aggregation. We demonstrated that epigallocatechin gallate (EGCG) form inter-molecular hydrogen bonds with each of IAPP and Aβ40. We also showed that EGCG reduced hetero-aggregate formation and resulted in lower β-sheets content and higher unordered structures in IAPP-Aβ40-EGCG samples. Importantly, we showed that EGCG is highly effective in reducing the toxicity of IAPP-Aβ40 hetero-aggregates on both cell models, specifically at concentrations that are equivalent to or are 2.5-fold higher than the mixed peptide concentrations. To the best of our knowledge, this is the first study to report the inhibition of IAPP-Aβ40 co-aggregation by small molecules. We conclude that EGCG is a promising candidate to prevent co-aggregation and cytotoxicity of IAPP-Aβ40, which in turn, contribute to the pathological link between AD and T2D.

Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis.

Our results reveal a novel mechanistic connection between brain metastasis and Alzheimer's disease, two previously unrelated pathologies; establish Aβ as a promising therapeutic target for brain metastasis; and demonstrate suppression of neuroinflammation as a critical feature of metastatic adaptation to the brain parenchyma. This article is highlighted in the In This Issue feature, p. 1171.

Site-Directed Chemical Modification of Amyloid by Polyoxometalates for Inhibition of Protein Misfolding and Aggregation.

Post-translational modification (PTM) of protein can significantly change protein conformation and function. Inspired by the natural PTM, we present a new approach to inhibit amyloid aggregation by chemical PTM modification. Polyoxometalates (POMs) were used as examples of inhibitors of β-amyloid peptide (Aβ) aggregation to illustrate the chemical PTM method. After the POMs were modified with thiazolidinethione (TZ), the resulting POMD-TZ acted as a chemical PTM agent and could covalently modify Aβ site-selectively at Lys16. Multiple biophysical techniques and biochemical assays have been employed to show the superiority of the chemical PTM method compared to traditional Aβ inhibitors. Since Aβ oligomers are more cytotoxic, we further functionalized POMD-TZ with an Aβ-targeted peptide and a fluorescent probe to obtain an "Aβ oligomer sensitive" probe. The use of PTM agents for the site-directed chemical modification of proteins provides a new way to regulate amyloid aggregation.

Site‐Directed Chemical Modification of Amyloid by Polyoxometalates for Inhibition of Protein Misfolding and Aggregation

AbstractPost‐translational modification (PTM) of protein can significantly change protein conformation and function. Inspired by the natural PTM, we present a new approach to inhibit amyloid aggregation by chemical PTM modification. Polyoxometalates (POMs) were used as examples of inhibitors of β‐amyloid peptide (Aβ) aggregation to illustrate the chemical PTM method. After the POMs were modified with thiazolidinethione (TZ), the resulting POMD‐TZ acted as a chemical PTM agent and could covalently modify Aβ site‐selectively at Lys16. Multiple biophysical techniques and biochemical assays have been employed to show the superiority of the chemical PTM method compared to traditional Aβ inhibitors. Since Aβ oligomers are more cytotoxic, we further functionalized POMD‐TZ with an Aβ‐targeted peptide and a fluorescent probe to obtain an “Aβ oligomer sensitive” probe. The use of PTM agents for the site‐directed chemical modification of proteins provides a new way to regulate amyloid aggregation.

Callistephin inhibits amyloid-β protein aggregation and determined cytotoxicity against cerebrovascular smooth muscle cells as an in vitro model of cerebral amyloid angiopathy

It has been indicated that amyloid β (Aβ) plaques can be accumulated within the basement membranes of cerebrovascular smooth muscle cells (CVSMCs) and stimulate the induction of cerebral amyloid angiopathy (CAA). However, the exact mechanism(s) of which small molecules including callistephin mitigate the formation of Aβ aggregation and associated CAA is not well-understood. Therefore, in the present study, Aβ 1–42 samples in the aggregation buffer were co-incubated for 36 h without or with of callistephin and the protein aggregation features along with the associated cytotoxicity against CVSMCs as the core components of cerebral arterial wall were explored by different biochemical and cellular methods. Fluorescence (ThT, Nile red) and CD techniques indicated the inhibition of Aβ 1–42 fibrillization in the presence of callistephin. Cellular assays revealed that cytotoxicity of Aβ 1–42 samples aged in the aggregation buffer with callistephin was much less against CVSMCs than Aβ 1–42 amyloid alone through regulation of membrane leakage and downregulation of TNF-α and IL-6 at protein level. In conclusion, these data may provide useful information about the possible mechanisms by which callistephin can show its protective effect against CAA.

Multi-Target Effects of Novel Synthetic Coumarin Derivatives Protecting Aβ-GFP SH-SY5Y Cells against Aβ Toxicity.

Alzheimer’s disease (AD) is a common neurodegenerative disease presenting with progressive memory and cognitive impairments. One of the pathogenic mechanisms of AD is attributed to the aggregation of misfolded amyloid β (Aβ), which induces neurotoxicity by reducing the expression of brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin-related kinase B (TRKB) and increasing oxidative stress, caspase-1, and acetylcholinesterase (AChE) activities. Here, we have found the potential of two novel synthetic coumarin derivatives, ZN014 and ZN015, for the inhibition of Aβ and neuroprotection in SH-SY5Y neuroblastoma cell models for AD. In SH-SY5Y cells expressing the GFP-tagged Aβ-folding reporter, both ZN compounds reduced Aβ aggregation, oxidative stress, activities of caspase-1 and AChE, as well as increased neurite outgrowth. By activating TRKB-mediated extracellular signal-regulated kinase (ERK) and AKT serine/threonine kinase 1 (AKT) signaling, these two ZN compounds also upregulated the cAMP-response-element binding protein (CREB) and its downstream BDNF and anti-apoptotic B-cell lymphoma 2 (BCL2). Knockdown of TRKB attenuated the neuroprotective effects of ZN014 and ZN015. A parallel artificial membrane permeability assay showed that ZN014 and ZN015 could be characterized as blood–brain barrier permeable. Our results suggest ZN014 and ZN015 as novel therapeutic candidates for AD and demonstrate that ZN014 and ZN015 reduce Aβ neurotoxicity via pleiotropic mechanisms.

Scaffold Searching of FDA and EMA-Approved Drugs Identifies Lead Candidates for Drug Repurposing in Alzheimer's Disease.

Clinical trials of novel therapeutics for Alzheimer’s Disease (AD) have consumed a significant amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and Drug Administration (FDA), European Medicines Agency (EMA), or Worldwide for another indication is a more rapid and less expensive option. Therefore, we apply the scaffold searching approach based on known amyloid-beta (Aβ) inhibitor tramiprosate to screen the DrugCentral database (n = 4,642) of clinically tested drugs. As a result, menadione bisulfite and camphotamide substances with protrombogenic and neurostimulation/cardioprotection effects were identified as promising Aβ inhibitors with an improved binding affinity (ΔGbind) and blood-brain barrier permeation (logBB). Finally, the data was also confirmed by molecular dynamics simulations using implicit solvation, in particular as Molecular Mechanics Generalized Born Surface Area (MM-GBSA) model. Overall, the proposed in silico pipeline can be implemented through the early stage rational drug design to nominate some lead candidates for AD, which will be further validated in vitro and in vivo, and, finally, in a clinical trial.

High-throughput screening for amyloid-β binding natural small-molecules based on the combinational use of biolayer interferometry and UHPLC−DAD-Q/TOF-MS/MS

Discovery of drugs rapidly and effectively is an important aspect for Alzheimer's disease (AD). In this study, a novel high-throughput screening (HTS) method aims at screening the small-molecules with amyloid-β (Aβ) binding affinity from natural medicines, based on the combinational use of biolayer interferometry (BLI) and ultra-high-performance liquid chromatography coupled with diode-array detector and quadrupole/time-of-flight tandem mass spectrometry (UHPLC−DAD-Q/TOF-MS/MS) has been firstly developed. Briefly, the components in natural medicines disassociated from biotinylated Aβ were collected to analyze their potential Aβ binding affinity by UHPLC−DAD-Q/TOF-MS/MS. Here, baicalein was confirmed to exhibit the highest binding affinity with Aβ in Scutellaria baicalensis. Moreover, polyporenic acid C (PPAC), dehydrotumulosic acid (DTA), and tumulosic acid (TA) in Kai-Xin-San (KXS) were also identified as potent Aβ inhibitors. Further bioactivity validations indicated that these compounds could inhibit Aβ fibrillation, improve the viability in Aβ-induced PC-12 cells, and decrease the Aβ content and improve the behavioral ability in Caenorhabditis elegans. The molecular docking results confirmed that PPAC, DTA, and TA possessed good binding properties with Aβ. Collectively, the present study has provided a novel and effective HTS method for the identification of natural inhibitors on Aβ fibrillation, which may accelerate the process on anti-AD drugs discovery and development.

Development of curcumin-based amyloid β aggregation inhibitors for Alzheimer's disease using the SAR matrix approach

Amyloid β (Aβ) aggregation inhibitor activity cliff involving a curcumin structure was predicted using the SAR Matrix method on the basis of 697 known Aβ inhibitors from ChEMBL (data set 2487). Among the compounds predicted, compound B was found to possess approximately 100 times higher inhibitory activity toward Aβ aggregation than curcumin. TEM images indicate that compound B induced the shortening of Aβ fibrils and increased the generation of Aβ oligomers in a concentration dependent manner. Furthermore, compound K, in which the methyl ester of compound B was replaced by the tert-butyl ester, possessed low cytotoxicity on N2A cells and attenuated Aβ-induced cytotoxicity, indicating that compound K would have an ability for preventing neurotoxicity caused by Aβ aggregation.

Neuroprotective Effect of Fucoxanthin against Intracerebroventricular Streptozotocin (ICV-STZ) Induced Cognitive Impairment in Experimental Rats.

Alzheimer's disease (AD) is a neurological disorder characterized by loss of memory and cognitive functions caused by oxidative stress, neuroinflammation, change in neurotransmitter levels, and excessive deposition of Aβ(1-42) plaques. Fucoxanthin is a carotenoid with potential antioxidant, anti-inflammatory, and neuroprotective actions. In the present study, fucoxanthin was employed as a protective strategy in Intracerebroventricular Streptozotocin (ICV-STZ) induced experimental model of cognitive impairment. STZ was injected twice ICV (3 mg/kg) on alternate days 1 and 3, and Wistar rats were evaluated for the memory analysis using Morris water maze and elevated plus-maze. Fucoxanthin at low 50 mg/kg, p.o. and high dose 100 mg/kg, p.o. was administered for 14 days. All animals were sacrificed on day 29, and brain hippocampus tissue after isolation was used for biochemical (MDA, nitrite, GSH, SOD and Catalase), neuroinflammatory (TNF-α, IL-1β, and IL-6), neurotransmitters (ACh, GABA Glutamate), Aβ(1-42) and Tau protein measurements. STZ-infused rats showed significant impairment in learning and memory, increased oxidative stress (MDA, nitrite), reduced antioxidant defense (GSH, SOD and Catalase), promoted cytokine release, and change in neurotransmitters level. However, fucoxanthin improved cognitive functions, restored antioxidant levels, reduced inflammatory markers dose-dependently, and restored neurotransmitters concentration. The finding of the current study suggests that fucoxanthin could be the promising compound for improving cognitive functions through antioxidant, anti-inflammatory, and neuroprotective mechanisms, and inhibition of acetylcholinesterase (AChE) enzyme activities, Aβ(1-42) accumulation, and tau protein.

Multipronged Regulatory Functions of Serum Albumin in Early Stages of Amyloid-β Aggregation.

Human serum albumin (HSA) is a major interacting-partner of Alzheimer's amyloid-β (Aβ) peptide in the plasma and has emerged as a promising therapeutic target. HSA inhibits Aβ fibrillization, but the underlying molecular mechanism is not well elucidated. In this work, we investigated the role of HSA in the early stages of Aβ aggregation by simulating the binding process of multiple Aβ monomers and protofibrils to HSA with extensive molecular dynamics simulations. HSA could simultaneously trap multiple Aβ monomers and accommodate the formation of nonfibrillar Aβ oligomers after binding. In particular, domains I and III show stronger binding capacities and hold preferable interaction sites for oligomers. Consequently, HSA prevents the formation of fibrillar oligomers in water, thus interfering with the nucleation process. On the other aspect, when protofibrils are preformed, HSA tends to block the β-strand spanning the central hydrophobic core located at the protofibril end, preventing the addition of monomers to protofibrils. Furthermore, Aβ protofibril structures are severely disrupted both globally and locally. Thus, further growth of protofibrils to fibrils is impeded by HSA. Our results collectively indicate that HSA performs multipronged regulatory functions in the early stages of Aβ aggregation. Our work advances the understanding of the amyloid inhibition of Aβ by HSA and provides theoretical guidance for developing rational therapies of Alzheimer's disease.

Inhibitory effect of an ethanol extract mixture of Aralia elata leaf, Chaenomeles sinensis fruit and Glycyrrhizae radix on Aβ (25–35)-induced memory impairment

The young shoots of Aralia elata, Chaenomeles sinensis fruit and Glycyrrhizae radix are edible and traditionally used as anti-inflammatory and antioxidant agents. The present study was performed to investigate the protective effect of an ethanol extract mixture of these three medicinal plants (ACG) against amyloid β protein (Aβ) (25–35)-induced memory impairment in an ICR mouse model. Memory impairment was induced by intracerebroventricular microinjection of 15 nmol Aβ (25–35) and assessed using the passive avoidance test and the Morris water maze test. The step-through latency in the passive avoidance test was decreased and the latency to reach the hidden platform in the Morris water maze test was increased in mice treated with Aβ (25–35), indicating memory impairment. This memory impairment induced by Aβ (25–35) was significantly prevented by chronic treatment with ACG (10, 25, and 50 mg/kg, p.o., 8 days). In memory impaired mice brain, cholinesterase activity and concentration of thiobarbituric acid reactive substance, a lipid peroxidation marker, were increased and glutathione level was decreased. These biochemical changes in Aβ (25–35)-treated mice were reversed by chronic administration of ACG. The present results suggest that antioxidant and anti-cholinesterase activities of ACG might be responsible for the inhibition of Aβ (25–35)-induced memory impairment and that ACG preparation may have a therapeutic role in preventing the progression of Alzheimer’s disease.

Dual Inhibitors of Amyloid-β and Tau Aggregation with Amyloid-β Disaggregating Properties: Extended In Cellulo, In Silico, and Kinetic Studies of Multifunctional Anti-Alzheimer’s Agents

In Alzheimer’s disease, neurons slowly degenerate due to the accumulation of misfolded amyloid β and tau proteins. In our research, we performed extended studies directed at amyloid β and tau aggregation inhibition using in cellulo (Escherichia coli model of protein aggregation), in silico, and in vitro kinetic studies. We tested our library of 1-benzylamino-2-hydroxyalkyl multifunctional anti-Alzheimer’s agents and identified very potent dual aggregation inhibitors. Among the tested derivatives, we selected compound 18, which exhibited a unique profile of biological activity. This compound was the most potent and balanced dual aggregation inhibitor (Aβ42 inhibition (inh.) 80.0%, tau inh. 68.3% in 10 μM), with previously reported in vitro inhibitory activity against hBuChE, hBACE1, and Aβ (hBuChE IC50 = 5.74 μM; hBACE1 IC50 = 41.6 μM; Aβ aggregation (aggr.) inh. IC50 = 3.09 μM). In docking studies for both proteins, we tried to explain the different structural requirements for the inhibition of Aβ vs tau. Moreover, docking and kinetic studies showed that compound 18 could inhibit the amyloid aggregation process at several steps and also displayed disaggregating properties. These results may help to design the next generations of dual or selective aggregation inhibitors.

Evaluating the Multifunctionality of a New Modulator of Zinc-Induced Aβ Aggregation Using a Novel Computational Approach.

The high concentration of zinc metal ions in Aβ aggregations is one of the most cited hallmarks of Alzheimer's disease (AD), and several substantial pieces of evidence emphasize the key role of zinc metal ions in the pathogenesis of AD. In this study, while designing a multifunctional peptide for simultaneous targeting Aβ aggregation and chelating the zinc metal ion, a novel and comprehensive approach is introduced for evaluating the multifunctionality of a multifunctional drugs based on computational methods. The multifunctional peptide consists of inhibitor and chelator domains, which are included in the C-terminal hydrophobic region of Aβ, and the first four amino acids of human albumin. The ability of the multifunctional peptide in zinc ion chelation has been investigated using molecular dynamics (MD) simulations of the peptide-zinc interaction for 300 ns, and Bennett's acceptance ratio (BAR) method has been used to accurately calculate the chelation free energy. Data analysis demonstrates that the peptide chelating domain can be stably linked to the zinc ion. Besides, the introduced method used for evaluating chelation and calculating the free energy of peptide binding to zinc ions was successfully validated by comparison with previous experimental and theoretical published data. The results indicate that the multifunctional peptide, coordinating with the zinc metal ion, can be effective in Aβ inhibition by preserving the native helical structure of the Aβ42 monomer as well as disrupting the β-sheet structure of Aβ42 aggregates. Detailed assessments of the Aβ42-peptide interactions elucidate that the inhibition of Aβ is achieved by considerable hydrophobic interactions and hydrogen bonding between the multifunctional peptide and the hydrophobic Aβ regions, along with interfering in stable bridges formed inside the Aβ aggregate.

Colorimetric determination of amyloid-β peptide using MOF-derived nanozyme based on porous ZnO-Co3O4 nanocages.

A sensitive and rapid colorimetric biosensor has been developed for determination of amyloid-β peptide (Aβ) and study ofamyloidogenesis based on the high peroxidase-like activity of porous bimetallic ZnO-Co3O4 nanocages (NCs). Due to the high binding ability of Aβ monomer to ZnO-Co3O4 NCs, the catalytic activity of ZnO-Co3O4 NCs can be significantly suppressed by Aβ monomer. This finding forms the basis for a colorimetric assay for Aβ monomer detection. The detection limit for Aβ monomer is 3.5nM with a linear range of 5 to 150nM (R2 = 0.997). The system was successfully applied to the determination of Aβ monomer in rat cerebrospinal fluid. Critically, the different inhibition effects of monomeric and aggregated Aβ species on the catalytic activity of ZnO-Co3O4 NCs enabled the sensor to be used for tracking the dynamic progress of Aβ aggregation and screening Aβ inhibitors. Compared with the commonly used thioflavin T fluorescence assay, this method provided higher sensitivity to the formation of Aβ oligomer at the very early assembly stage. Our assay shows potential application in early diagnosis and therapy of Alzheimer's disease (AD).

Curcumin Inhibits the Primary Nucleation of Amyloid-Beta Peptide: A Molecular Dynamics Study.

The amyloid plaques are a key hallmark of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Amyloidogenesis is a complex long-lasting multiphase process starting with the formation of nuclei of amyloid peptides: a process assigned as a primary nucleation. Curcumin (CU) is a well-known inhibitor of the aggregation of amyloid-beta (Aβ) peptides. Even more, CU is able to disintegrate preformed Aβ firbils and amyloid plaques. Here, we simulate by molecular dynamics the primary nucleation process of 12 Aβ peptides and investigate the effects of CU on the process. We found that CU molecules intercalate among the Aβ chains and bind tightly to them by hydrogen bonds, hydrophobic, π–π, and cation–π interactions. In the presence of CU, the Aβ peptides form a primary nucleus of a bigger size. The peptide chains in the nucleus become less flexible and more disordered, and the number of non-native contacts and hydrogen bonds between them decreases. For comparison, the effects of the weaker Aβ inhibitor ferulic acid (FA) on the primary nucleation are also examined. Our study is in good agreement with the observation that taken regularly, CU is able to prevent or at least delay the onset of neurodegenerative disorders.

Lychee seed polyphenol protects the blood-brain barrier through inhibiting Aβ(25-35)-induced NLRP3 inflammasome activation via the AMPK/mTOR/ULK1-mediated autophagy in bEnd.3 cells and APP/PS1 mice.

Blood-brain barrier (BBB) dysfunction has been implicated in Alzheimer's disease (AD) and is closely linked to the release of proinflammatory cytokines in brain capillary endothelial cells. We have previously reported that lychee seed polyphenols (LSP) exerted anti-neuroinflammatory effect. In this study, we aimed to explore the protective effect of LSP on BBB integrity. The monolayer permeability of bEnd.3 cells, and the mRNA level and protein expression of tight junction proteins (TJs), including Claudin 5, Occludin, and ZO-1, were examined. In addition, the inhibition of Aβ(25-35)-induced NLRP3 inflammasome activation, and the autophagy induced by LSP were investigated by detecting the expression of NLRP3, caspase-1, ASC, LC3, AMPK, mTOR, and ULK1. Furthermore, the cognitive function and the expression of TJs, NLRP3, caspase-1, IL-1β, and p62 were determined in APP/PS1 mice. The results showed that LSP significantly decreased the monolayer permeability and inhibited the NLRP3 inflammasome in Aβ(25-35)-induced bEnd3 cells. In addition, LSP induced autophagy via the AMPK/mTOR/ULK1 pathway in bEnd.3 cells, and improved the spatial learning and memory function, increased the TJs expression, and inhibited the expression of NLRP3, caspase-1, IL-1β, and p62 in APP/PS1 mice. Therefore, LSP protects BBB integrity in AD through inhibiting Aβ(25-35)-induced NLRP3 inflammasome activation via the AMPK/mTOR/ULK1-mediated autophagy.