Accumulation Of Amyloid-β Peptide Research Articles

Organic Chimeras based on Selenosugars, Steroids, and Fullerenes as Potential Inhibitors of the β-amyloid Peptide Aggregation.

The aggregation of β-amyloid peptide (Aβ) is associated with neurodegenerative diseases such as Alzheimer's disease (AD). Several therapies aimed at reducing the aggregation of this peptide have emerged as potential strategies for the treatment of AD. This paper describes the design and preparation of new hybrid molecules based on steroids, selenosugars, and [60]fullerene as potential inhibitors of Aβ oligomerization. These moieties were selected based on their antioxidant properties and possible areas of interaction with the Aβ. Cyclopropanations between C60 and malonates bearing different steroid and selenosugar moieties using the Bingel-Hirsch protocol have enabled the synthesis of functionalized molecular hybrids. The obtained derivatives were characterized by physical and spectroscopic techniques. Theoretical calculations for all the selenium compounds were performed using the density functional theory DFT/B3LYP-D3(BJ)/6-311G(2d,p) predicting the most stable conformations of the synthesized derivatives. Relevant geometrical parameters were investigated to relate the stereochemical behavior and the spectroscopic data obtained. The affinity of the compounds for Aβ-peptide was estimated by molecular docking simulation, which predicted an increase in affinity and interactions for Aβ for the hybrids containing the C60 core. In addition, parameters such as lipophilicity, polar surface area, and dipole moment were calculated to predict their potential interaction with membrane cells.

Phosphorylated tau in cerebrospinal fluid-derived extracellular vesicles in Alzheimer’s disease: a pilot study

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder characterized by brain aggregation of β-amyloid (Aβ) peptides and phosphorylated tau (P-tau) proteins. Extracellular vesicles (EVs) can be isolated and studied for potential roles in disease. While several studies have tested plasma-derived EVs in AD, few have analyzed EVs from cerebrospinal fluid (CSF), which are potentially more closely related to brain changes. This study included 20 AD patients and 20 cognitively unimpaired (CU) participants. Using a novel EV isolation method based on acoustic trapping, we isolated and purified EVs from minimal CSF volumes. EVs were lysed and analyzed by immunoassays for P-tau217 and P-tau181. Isolation was confirmed through transmission electron microscopy and the presence of EV-specific markers (CD9, CD63, CD81, ATP1A3). Nanoparticle tracking analysis revealed a high variance in EV distribution. AD patients exhibited increased P-tau181 and decreased P-tau217 in EVs, leading to a higher EV P-tau181/P-tau217 ratio compared to CU. No significant differences in EV counts or sizes were observed between AD and CU groups. This study is the first to use acoustic trapping to isolate EVs from CSF and demonstrates differential P-tau content in AD-derived EVs, warranting further research to understand the relationship between these EV changes and brain pathology.

Inhibition of amyloid beta oligomer, fibrils, and peptide using nanoparticles to disrupt Alzheimer's pathogenesis.

The Aβ peptide, which is connected to the development of Alzheimer's disease, forms highly neurotoxic prefibrillar oligomeric aggregates, which are challenging to study due to their fleeting, low prevalence, and diverse nature. These aggregates are considered to play a role in the pathogenesis of numerous neurodegenerative diseases. The potential approach of blocking or disrupting the buildup of amyloid peptides, particularly amyloid-β (AβOs), by using nanoparticles that specifically bind or prevent their aggregation to develop new medications and treatments for Alzheimer's disease (AD) could be a promising solution. Nanoparticles have been proposed as a potential solution to modify the protein fibrillation process. Recently, Researchers have design and created some nanoparticles for inhibition of amyloid-β oligomer and (Aβ) peptide aggregation, involved in Alzheimer’s disease (AD). In this concise review, we concentrated on the mechanism and formation of amyloid beta oligomers, fibrils, peptides, and it’s role in Alzheimer's disease. Secondly, we discussed small molecules that can detect various forms of amyloid beta for early diagnosis. Lastly, we primarily focused on nanoparticles that possess the ability to inhibit and disaggregate amyloid beta oligomers fibrils, and peptide which are the primary hallmarks of Alzheimer's disease. Here for the first time we also summarize some of the nanoparticles and nanomaterials which can dis-aggregate the exis-ting amyloid-β oligomer and (Aβ) peptide which are challenging for many researcher.

Modulation of the Nogo signaling pathway to overcome amyloid-β-mediated neurite inhibition in human pluripotent stem cell-derived neurites.

Neuronal cell death and the loss of connectivity are two of the primary pathological mechanisms underlying Alzheimer's disease. The accumulation of amyloid-β peptides, a key hallmark of Alzheimer's disease, is believed to induce neuritic abnormalities, including reduced growth, extension, and abnormal growth cone morphology, all of which contribute to decreased connectivity. However, the precise cellular and molecular mechanisms governing this response remain unknown. In this study, we used an innovative approach to demonstrate the effect of amyloid-β on neurite dynamics in both two-dimensional and three-dimensional culture systems, in order to provide more physiologically relevant culture geometry. We utilized various methodologies, including the addition of exogenous amyloid-β peptides to the culture medium, growth substrate coating, and the utilization of human-induced pluripotent stem cell technology, to investigate the effect of endogenous amyloid-β secretion on neurite outgrowth, thus paving the way for potential future applications in personalized medicine. Additionally, we also explore the involvement of the Nogo signaling cascade in amyloid-β-induced neurite inhibition. We demonstrate that inhibition of downstream ROCK and RhoA components of the Nogo signaling pathway, achieved through modulation with Y-27632 (a ROCK inhibitor) and Ibuprofen (a Rho A inhibitor), respectively, can restore and even enhance neuronal connectivity in the presence of amyloid-β. In summary, this study not only presents a novel culture approach that offers insights into the biological process of neurite growth and inhibition, but also proposes a specific mechanism for reduced neural connectivity in the presence of amyloid-β peptides, along with potential intervention points to restore neurite growth. Thereby, we aim to establish a culture system that has the potential to serve as an assay for measuring preclinical, predictive outcomes of drugs and their ability to promote neurite outgrowth, both generally and in a patient-specific manner.

Influence of resveratrol on the sorption of phosphorylated tau protein and MAPT on the PVDF membrane in a mouse model of Alzheimer’s disease

Alzheimer’s disease is a complex neurodegenerative disease based on various processes associated with the accumulation and aggregation of defective proteins. Among them, the particularly important ones are the following: amyloid-β, which is formed by the breakdown of amyloid precursor protein, the accumulation of hyperphosphorylated tau proteins inside neurons that form neurofibrillary tangles, and aberrant aggregation and inclusion formation of microtubule-associated protein tau (MAPT). APP/PS1 transgenic mice act as a model of Alzheimer’s disease and express mutant human genes that cause the accumulation of amyloid-β peptides in the brain. The goal of this work was a quantitative assessment of the level of p-tau231 in the brain of transgenic mice with a model of AD using the sorption method. The objectives of the study also included testing the ability of the natural polyphenol resveratrol to reduce the concentration of p-tau231 in the brain of transgenic mice and improve their cognitive functions. Western blot is a widely used method for the immunodetection and in vitro quantitative determination of proteins. Western blot allows separating proteins based on their molecular weight with the further transfer to an adsorption membrane. In this case, the proteins are transferred from the gel to the PVDF membrane using electrophoretic elution. This method involves placing a protein-containing polyacrylamide gel in direct contact with a PVDF membrane represented by a linear polymer with repetitive links -(CF2-CH2)-. Proteins transferred to the membrane are well-retained on its surface during the whole immunodetection process due to a combination of dipole and hydrophobic interactions. Western blot showed that mice with impaired protein aggregation accumulated significantly more MAPT and phosphorylated tau protein in the brain as compared to wild mice. In addition, in the course of the Morris water maze test, these mice showed cognitive deficits, which manifested both in the difficulty of finding the platform and more anxious behaviour, which confirmed pronounced thigmotaxis. The natural polyphenol resveratrol partially reversed cognitive deficits, although this effect was not associated with decreased levels of phosphorylated tau and MAPT.

Characterization of Olive Oil Phenolic Extracts and Their Effects on the Aggregation of the Alzheimer's Amyloid-β Peptide and Tau.

The dietary consumption of extra virgin olive oil (EVOO) is believed to slow the progression of Alzheimer's disease (AD) symptoms. Its protective mechanisms are unclear, but specific EVOO phenolic compounds can individually impede the aggregation of amyloid-β (Aβ) peptides and the microtubule-associated protein tau, two important pathological manifestations of AD. It is unknown, however, whether the numerous and variable phenolic compounds that are consumed in dietary EVOO can collectively alter tau and Aβ aggregation as effectively as the individual compounds. The activity of these complex mixtures against Aβ and tau may be moderated by competition between active and nonactive phenolic components and by extensive derivatizations and isomerization. Here, phenolic mixtures extracted from two different EVOO sources are characterized and tested for how they modulate the aggregation of Aβ40 peptide and tau peptides in vitro. The chromatographic and NMR analysis of Greek and Saudi Arabian EVOO phenolic extracts reveals that they have different concentration profiles, and over 30 compounds are identified. Thioflavin T fluorescence and circular dichroism measurements show that relatively low concentrations (<20 μg/mL) of the Greek and Saudi extracts reduce the rate of Aβ40 aggregation and fibril mass, despite the extracts having different phenolic profiles. By contrast, the Greek extract reduces the rate of tau aggregation only at very high phenolic concentrations (>100 μg/mL). Most compounds in the extracts bind to preformed Aβ40 fibrils and release soluble Aβ oligomers that are mildly toxic to SH-SY5Y cells. Much higher (500 μg/mL) extract concentrations are required to remodel tau filaments into oligomers, and a minimal binding of phenolic compounds to the preformed filaments is observed. It is concluded that EVOO extracts having different phenol profiles are similarly capable of modulating Aβ40 aggregation and fibril morphology in vitro at relatively low concentrations but are less efficient at modulating tau aggregation. Over 2 M tonnes of EVOO are consumed globally each year as part of the Mediterranean diet, and the results here provide motivation for further clinical interrogation of the antiaggregation properties of EVOO as a potential protective mechanism against AD.

Lutein from Chicken Eggs Prevents Amyloid β-Peptide Aggregation In Vitro and Amyloid β-Induced Inflammation in Human Macrophages (THP-1).

Epidemiological studies predict that chicken eggs contain constituents other than proteins that prevent Alzheimer's disease. This study screened for constituents that inhibit the aggregation of amyloid β peptide (Aβ)1-42 and elucidated their mechanisms to explore the active components of chicken eggs. Thioflavin T assays and transmission electron microscopy observations showed that arachidonic acid (ARA), lysophosphatidylcholine, lutein (LTN), palmitoleic acid, and zeaxanthin inhibited Aβ aggregation. Among these, ARA and LTN showed the highest activity. Photoinduced cross-linking of unmodified protein assays and infrared absorption spectrometry measurements showed that LTN strongly inhibited highly toxic Aβ1-42 protofibril formation. Furthermore, LTN suppressed Aβ1-42-induced IL 1B and TNF expression in human macrophage-like cells. In summary, LTN plays a crucial role in the AD-preventive effect of chicken eggs by suppressing Aβ1-42 aggregation and Aβ1-42-induced inflammation.

Amylovis-201 is a new dual-target ligand, acting as an anti-amyloidogenic compound and a potent agonist of the σ1 chaperone protein

The aggregation of Amyloid-β (Aβ) peptides is associated with neurodegeneration in Alzheimer's disease (AD). We previously identified novel naphtalene derivatives, including the lead compound Amylovis-201, able to form thermodynamically stable complexes with Aβ species, peptides and fibrils. As the drug showed a chemical scaffold coherent for an effective interaction with the σ1 receptor chaperone and as σ1 agonists are currently developed as potent neuroprotectants in AD, we investigated the pharmacological action of Amylovis-201 on the σ1 receptor. We report that Amylovis-201 is a potent σ1 agonist by several in silico, in vitro and in vivo assays and that its anti-amnesic and neuroprotective effects involve a pharmacological action at σ1 receptors. Furthermore, we show for the first time that classical σ1 receptor agonist (PRE-084), and antagonist (NE-100) are able to interact and disaggregate Aβ25–35 fibrils. Interestingly, Amylovis-201 was the only compound inhibiting Aβ25–35 aggregates formation. Our results therefore highlight a dual action of Amylovis-201 as anti-aggregating agent and σ1 receptor agonist that could be highly effective in long-term treatment against neurodegeneration in AD.

Amino-terminally elongated Aβ peptides are generated by the secreted metalloprotease ADAMTS4 and deposit in a subset of Alzheimer's disease brains.

The aggregation and deposition of amyloid-β (Aβ) peptides in the brain is thought to be the initial driver in the pathogenesis of Alzheimer's disease (AD). Aside from full-length Aβ peptides starting with an aspartate residue in position 1, both N-terminally truncated and elongated Aβ peptides are produced by various proteases from the amyloid precursor protein (APP) and have been detected in brain tissues and body fluids. Recently, we demonstrated that the particularly abundant N-terminally truncated Aβ4-x peptides are generated by ADAMTS4, a secreted metalloprotease that is exclusively expressed in the oligodendrocyte cell population. In this study, we investigated whether ADAMTS4 might also be involved in the generation of N-terminally elongated Aβ peptides. We used cell-free and cell-based assays in combination with matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF) and electrochemiluminescence sandwich immunoassays to identify and quantify N-terminally elongated Aβ peptide variants. Antibodies against these Aβ variants were characterised by peptide microarrays and employed for the immunohistochemical analyses of human brain samples. In this study, we discovered additional ADAMTS4 cleavage sites in APP. These were located N-terminal to Asp-(1) in the Aβ peptide sequence between residues Glu-(-7) and Ile-(-6) as well as Glu-(-4) and Val-(-3), resulting in the release of N-terminally elongated Aβ-6-x and Aβ-3-x peptides, of which the latter serve as a component in a promising Aβ-based plasma biomarker. Aβ-6/-3-40 peptides were detected in supernatants of various cell lines and in the cerebrospinal fluid (CSF), and ADAMTS4 enzyme activity promoted the release of Aβ-6/-3-x peptides. Furthermore, by immunohistochemistry, a subset of AD cases displayed evidence of extracellular and vascular localization of N-terminally elongated Aβ-6/-3-x peptides. The current findings implicate ADAMTS4 in both the pathological process of Aβ peptide aggregation and in the early detection of amyloid pathology in AD.

Acute Hyperglycemia Induced by Hyperglycemic Clamp Affects Plasma Amyloid-β in Type 2 Diabetes.

Individuals with type 2 diabetes (T2D) have an increased risk of cognitive symptoms and Alzheimer's disease (AD). Mis-metabolism with aggregation of amyloid-β peptides (Aβ) play a key role in AD pathophysiology. Therefore, human studies on Aβ metabolism and T2D are warranted. The objective of this study was to examine whether acute hyperglycemia affects plasma Aβ1-40 and Aβ1-42 concentrations in individuals with T2D and matched controls. Ten participants with T2D and 11 controls (median age, 69 years; range, 66-72 years) underwent hyperglycemic clamp and placebo clamp (saline infusion) in a randomized order, each lasting 4 hours. Aβ1-40, Aβ1-42, and insulin-degrading enzyme (IDE) plasma concentrations were measured in blood samples taken at 0 and 4 hours of each clamp. Linear mixed-effect regression models were used to evaluate the 4-hour changes in Aβ1-40 and Aβ1-42 concentrations, adjusting for body mass index, estimated glomerular filtration rate, and 4-hour change in insulin concentration. At baseline, Aβ1-40 and Aβ1-42 concentrations did not differ between the two groups. During the hyperglycemic clamp, Aβ decreased in the control group, compared to the placebo clamp (Aβ1-40: p = 0.034, Aβ1-42: p = 0.020), IDE increased (p = 0.016) during the hyperglycemic clamp, whereas no significant changes in either Aβ or IDE was noted in the T2D group. Clamp-induced hyperglycemia was associated with increased IDE levels and enhanced Aβ40 and Aβ42 clearance in controls, but not in individuals with T2D. We hypothesize that insulin-degrading enzyme was inhibited during hyperglycemic conditions in people with T2D.

Modeling the Effects of Cell Stress and Ca2+ Dysregulation on the Crosstalk Between Apoptosis and Autophagy in Neurodegenerative Diseases

BACKGROUND: Apoptosis is a highly regulated and irreversible process of cell death, while autophagy maintains cellular homeostasis by degrading and recycling cytoplasmic components, such as aggregated and damaged proteins (Elmore, 2007; Glick et al., 2010). Dysregulation of both processes is observed in neurodegenerative diseases (NDs) (Ghavami et al., 2014). For example, in Alzheimer’s disease (AD), accumulation of amyloid-β peptides is attributed to dysregulated autophagy (Han et al., 2020). Dysregulated autophagy can further induce apoptosis and neurodegeneration (Chung et al., 2018). Although studies have focused on signaling pathways involved in apoptosis and autophagy extensively in other cell types, an effective framework to clarify their interplay in the nervous system is lacking. Here we develop a simplified network model of the key pathways involved in apoptosis and autophagy to study their interplay and dysregulation in NDs. Specifically, we model triggers such as cell stress and Ca2+ dysregulation implicated in aging and NDs and simulate their effects on cell fate. Although much of the empirical support to model development came from studies in other cell types, our integrative framework of the ubiquitous and non-cell autonomous pathways can offer deeper insights into the pathophysiology in NDs. METHODS: Ordinary differential equations (ODEs) were used to model the network of molecular compartments, and the rates of change in their abundances and interactions. The interconnections between these compartments, for example, the inhibitory role of caspases on autophagy-inducing Beclin-1(BECN1), are validated in empirical work and adopted in previous modeling studies (Bogdał et al., 2013; Fan and Zong, 2013; Mariño et al., 2014; Tavassoly et al., 2015; Wirawan et al., 2010; Yin et al., 2017). MATLAB was used to code and simulate the model; ode45 was the numerical integration method of choice. RESULTS: We developed an integrative framework for the signaling pathways of apoptosis and autophagy. Our model adapted and merged three previously reported dynamic network models (Bogdal et al., 2013; Tavassoly et al., 2015; Yin et al., 2017) which also included pathways relevant to NDs. A hypothetical cell stress input and cytosolic Ca2+ concentration in our network model represent extrinsic and intrinsic triggers respectively. Using such a computational approach, we are investigating the multiplexing role of Beclin 1 protein (part of Bcl-2 protein family), mTOR (mammalian target of rapamycin) kinase and JNK (Jun N-terminal kinase) in the synergy between autophagy and apoptosis. Simulation experiments are underway to predict the mechanisms of cell vulnerability versus resilience implicated in NDs involving these pathways. CONCLUSION: Our network provides a framework based on which experiments can be designed to validate model predictions and better understand the dynamic processes involved in NDs. Although NDs are complex and chronic, understanding the effects of common triggers such as cell stress and disrupted Ca2+ homeostasis on cell fate determination is critical to slow ND progression. Therefore, our study delineating the dynamic crosstalk between apoptosis and autophagy offers crucial insights into ND pathophysiology and suggests specific protein targets within these key common pathways. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Beta-amyloid plaque deposits and increased tau protein in the early diagnosis of alzheimer’s disease: the importance of physical activity in the prevention and evolution of the patient

In recent years, it has become clear that the β-amyloid (Aβ) component of senile plaques may be the key molecule in the pathology of Alzheimer's disease (AD). However, the origin and site of Aβ's neurotoxic action are still the subject of controversy. The precursor of the β-amyloid peptide is the β-amyloid precursor protein, which is predominantly neuronal. The hypothesis is that intraneuronal dysregulation of Amyloid Precursor Protein (APP) leads to the accumulation of Aβ peptides in intracellular compartments. This accumulation impairs the trafficking of APP, which initiates a cascade of pathological changes and causes the degeneration of pyramidal neurons. The increased secretion of Aβ as a function of stressed neurons and degenerated neuron remnants provides seeds for extracellular Aβ aggregates, which induce secondary degenerative events involving neighboring cells such as neurons, astroglia and macrophages/microglia. The benefits of physical exercise to reduce low-grade inflammation and improve cognitive function have become a growing field of interest. Epidemiological research has shown that a sedentary lifestyle intensifies the processes of disability and dependence, and also increases the incidence of chronic diseases. Physical exercise has been inversely associated with high levels of different inflammatory markers. It plays a neurotrophic role, capable of promoting a reduction in the accumulation of β-amyloid peptide and the hyperphosphorylation of tau protein, being an important alternative pathway for reducing the degenerative process, which does not result in the release of pro-inflammatory factors, as well as helping to reduce the levels of pro-inflammatory cytokines and improve peripheral concentrations.

Effect of caffeine on the aggregation of amyloid-β-A 3D RISM study.

Alzheimer's disease is a detrimental neurological disorder caused by the formation of amyloid fibrils due to the aggregation of amyloid-β peptide. The primary therapeutic approaches for treating Alzheimer's disease are targeted to prevent this amyloid fibril formation using potential inhibitor molecules. The discovery of such inhibitor molecules poses a formidable challenge to the design of anti-amyloid drugs. This study investigates the effect of caffeine on dimer formation of the full-length amyloid-β using a combined approach of all-atom, explicit water molecular dynamics simulations and the three-dimensional reference interaction site model theory. The change in the hydration free energy of amyloid-β dimer, with and without the inhibitor molecules, is calculated with respect to the monomeric amyloid-β, where the hydration free energy is decomposed into energetic and entropic components, respectively. Dimerization is accompanied by a positive change in the partial molar volume. Dimer formation is spontaneous, which implies a decrease in the hydration free energy. However, a reverse trend is observed for the dimer with inhibitor molecules. It is observed that the negatively charged residues primarily contribute for the formation of the amyloid-β dimer. A residue-wise decomposition reveals that hydration/dehydration of the side-chain atoms of the charged amino acid residues primarily contribute to dimerization.

Novel 6-alkyl-bridged 4-arylalkylpiperazin-1-yl derivatives of azepino[4,3-b]indol-1(2H)-one as potent BChE-selective inhibitors showing protective effects against neurodegenerative insults

Due to the putative role of butyrylcholinesterase (BChE) in regulation of acetylcholine levels and functions in the late stages of the Alzheimer's disease (AD), the potential of selective inhibitors (BChEIs) has been envisaged as an alternative to administration of acetylcholinesterase inhibitors (AChEIs). Starting from our recent findings, herein the synthesis and in vitro evaluation of cholinesterase (ChE) inhibition of a novel series of some twenty 3,4,5,6-tetrahydroazepino[4,3-b]indol-1(2H)-one derivatives, bearing at the indole nitrogen diverse alkyl-bridged 4-arylalkylpiperazin-1-yl chains, are reported. The length of the spacers, as well as the type of arylalkyl group affected the enzyme inhibition potency and BChE/AChE selectivity. Two compounds, namely 14c (IC50 = 163 nM) and 14d (IC50 = 65 nM), bearing at the nitrogen atom in position 6 a n-pentyl- or n-heptyl-bridged 4-phenethylpiperazin-1-yl chains, respectively, proved to be highly potent mixed-type inhibitors of both equine and human BChE isoforms, showing more than two order magnitude of selectivity over AChE. The study of binding kinetics through surface plasmon resonance (SPR) highlighted differences in their BChE residence times (8 and 47 s for 14c and 14d, respectively). Moreover, 14c and 14d proved to hit other mechanisms known to trigger neurodegeneration underlying AD and other CNS disorders. Unlike 14c, compound 14d proved also capable of inhibiting by more than 60% the in vitro self-induced aggregation of neurotoxic amyloid-β (Aβ) peptide at 100 μM concentration. On the other hand, 14c was slightly better than 14d in counteracting, at 1 and 10 μM concentration, glutamate excitotoxicity, due to over-excitation of NMDA receptors, and hydrogen peroxide-induced oxidative stress assessed in neuroblastoma cell line SH-SY5Y. This paper is dedicated to Prof. Marcello Ferappi, former dean of the Faculty of Pharmacy of the University of Bari, in the occasion of his 90th birthday.

Aging and brain free cholesterol concentration on amyloid-β peptide accumulation in guinea pigs.

Alzheimer's disease is a complex multifactorial neurodegenerative disorder wherein age is a major risk factor. The appropriateness of the Hartley guinea pig (GP), which displays high sequence homologies of its amyloid-β (Aβ40 and Aβ42) peptides, Mdr1 and APP(amyloid precursor protein) and similarity in lipid handling to humans, was appraised among 9-40weeks old guinea pigs. Protein expression levels of P-gp (Abcb1) and Cyp46a1 (24(S)-hydroxylase) for Aβ40, and Aβ42 efflux and cholesterol metabolism, respectively, were decreased with age, whereas those for Lrp1 (low-density lipoprotein receptor related protein 1), Rage (receptor for advanced glycation endproducts) for Aβ efflux and influx, respectively, and Abca1 (the ATP binding cassette subfamily A member 1) for cholesterol efflux, were unchanged among the ages examined. There was a strong, negative correlation of the brain Aβ peptide concentrations and Abca1 protein expression levels with free cholesterol. The correlation of Aβ peptide concentrations with Cyp46a1 was, however, not significant, and concentrations of the 24(S)-hydroxycholesterol metabolite revealed a decreasing trend from 20weeks old toward 40weeks old guinea pigs. The composite data suggest a role for free cholesterol on brain Aβ accumulation. The decreases in P-gp and Lrp1 protein levels should further exacerbate the accumulation of Aβ peptides in guinea pig brain.

Astemizole, a Second-Generation Histamine H1-Receptor Antagonist, Did Not Attenuate the Aggregation Process of α-Synuclein In Vitro.

The antihistamine astemizole has shown disease-modifying effects in several preclinical disease models of Parkinson's disease (PD). Astemizole also interacts with an anomalous aggregation of Alzheimer's disease-related amyloid-β (Aβ) peptide and has inhibitory activity on the human prion protein PrPSc. We hypothesized that the proposed preclinical benefits of astemizole on PD can be associated with the attenuation of pathological α-synuclein (α-syn) aggregation. We tested the effects of astemizole on the fibrillation processes of amyloid peptides using thioflavin T aggregation monitoring, Congo red spectral analysis, cell viability study, and transmission electron microscopic imaging. We found that astemizole did not inhibit α-syn aggregation in vitro even at a high molar ratio but inhibited the assembly of Aβ aggregates. Our results suggest that the inhibitory effect of astemizole on amyloid formation is target-protein selective, and the proposed beneficial effects of this compound observed in translational PD models might not be due to its ameliorating effects on α-syn aggregation.

Molecular Insights into the Inhibition and Disaggregation Effects of EGCG on Aβ40 and Aβ42 Cofibrillation.

The misfolding and aggregation of amyloid-β (Aβ) peptides play a pivotal role in the pathogenesis of Alzheimer's disease (AD). Aβ40 and Aβ42, the two primary isoforms of Aβ, can not only self-aggregate into homogeneous aggregates but also coaggregate to form mixed fibrils. Epigallocatechin-3-gallate (EGCG), a prominent tea polyphenol, has shown the capability to prevent the self-aggregation of Aβ40 and Aβ42 peptides and disaggregate their homogeneous fibrils. However, its effects on the cofibrillation of Aβ40 and Aβ42 have not yet been explored. Here, we employed molecular dynamic simulations to investigate the effects of EGCG on the coaggregation of Aβ40 and Aβ42, as well as on their mixed fibril. Our findings indicated that EGCG effectively inhibits the codimerization of Aβ40 and Aβ42 primarily by impeding the interchain interaction between the two isoforms. The key binding sites for EGCG on Aβ40 and Aβ42 are the polar residues and aromatic residues, engaging in hydrogen-bond , π-π, and cation-π interactions with EGCG. Additionally, EGCG disaggregates the Aβ40-Aβ42 mixed fibril by reducing its long-range interaction through similar binding sites and interactions as those between EGCG and Aβ40-Aβ42 heterodimers. Our research reveals the comprehensive inhibition and disaggregation effects of EGCG on the cofibrillation of Aβ isoforms, which provides further support for the development of EGCG as an effective antiaggregation agent for AD.

In Silico Exploration of APOE4 Inhibitors: Molecular Docking and ADMET Profiling for Alzheimer's Therapy

Background: Alzheimer's disease (AD), a prevalent neurodegenerative disorder, poses significant challenges to healthcare systems worldwide. The aggregation of Amyloid-β peptide and the presence of apolipoprotein E4 (apoE4) are recognized as central factors in AD pathogenesis. Despite the availability of FDA-approved drugs, there remains a dire need for more effective and targeted treatments to combat this disease. The advent of in silico methodologies offers a promising avenue for accelerating the drug discovery process, providing a cost-effective and efficient means to screen for potential therapeutic agents. Objective: This study aimed to identify and evaluate potential inhibitors of apoE4 using in silico drug discovery methods. By targeting the interaction domain of apoE4, the study sought to discover compounds capable of reducing beta-amyloid aggregation, thus offering a novel approach to AD therapy. Methods: Computational techniques, including the Lipinski Rule of Five and ADMET filtering, were employed to screen a dataset of 80 chemical inhibitors retrieved from the NCBI database. Molecular docking was performed to assess the binding affinities and orientations of the compounds to apoE4, utilizing Phyre2 for 3D structure prediction and AutoDock Vina for docking simulations. The selection criteria for lead compounds were based on their binding energy, hydrogen bonding interactions, and compliance with drug-like properties. Results: Out of the initial 80 compounds screened, 15 were excluded based on the Lipinski Rule of Five, and an additional 43 were deemed unsuitable following ADMET analysis. Molecular docking identified two compounds, taxifolin and luteolin, exhibiting superior binding affinities to apoE4, with taxifolin showing the lowest binding energy of -7.4 kcal/mol and the highest number of hydrogen bonds in one of its conformations. Conclusion: The study successfully leveraged in silico methods to identify taxifolin and luteolin as potent inhibitors of apoE4, highlighting the potential of computational drug discovery in developing novel AD therapies. These findings pave the way for future experimental validation and clinical trials to assess the therapeutic efficacy and safety of these compounds in treating Alzheimer's disease.

Development of Neuroprotective Agents for the Treatment of Alzheimer's Disease using Conjugates of Serotonin with Sesquiterpene Lactones.

Sesquiterpene lactones are secondary plant metabolites with a wide variety of biological activities. The process of lactone conjugation to other pharmacophores can increase the efficacy and specificity of the conjugated agent effect on molecular targets in various diseases, including brain pathologies. Derivatives of biogenic indoles, including neurotransmitter serotonin, are of considerable interest as potential pharmacophores. Most of these compounds have neurotropic activity and, therefore, can be used in the synthesis of new drugs with neuroprotective properties. The aim of this experimental synthesis was to generate potential treatment agents for Alzheimer's disease using serotonin conjugated with natural sesquiterpene lactones. Three novel compounds were obtained via the Michael reaction and used for biological testing. The obtained conjugates demonstrated complex neuroprotective activities. Serotonin conjugated to isoalantolactone exhibited strong antioxidant and mitoprotective activities. The agent was also found to inhibit β-site amyloid precursor protein cleaving enzyme 1 (BACE-1), prevent the aggregation of β-amyloid peptide 1-42, and protect SH-SY5Y neuroblastoma cells from neurotoxins such as glutamate and H2O2. In a transgenic animal model of Alzheimer's disease (5xFAD line), the conjugated agent restored declined cognitive functions and improved learning and memory. In conclusion, the obtained results indicate that serotonin conjugates to sesquiterpene lactones are promising agents for the treatment of symptoms associated with Alzheimer's disease.

Impact of nanoplastics on Alzheimer ’s disease: Enhanced amyloid-β peptide aggregation and augmented neurotoxicity

Nanoplastics, widely existing in the environment and organisms, have been proven to cross the blood-brain barrier, increasing the incidence of neurodegenerative diseases like Alzheimer’s disease (AD). However, current studies mainly focus on the neurotoxicity of nanoplastics themselves, neglecting their synergistic effects with other biomolecules and the resulting neurotoxicity. Amyloid β peptide (Aβ), which triggers neurotoxicity through its self-aggregation, is the paramount pathogenic protein in AD. Here, employing polystyrene nanoparticles (PS) as a model for nanoplastics, we reveal that 100 pM PS nanoparticles significantly accelerate the nucleation rate of two Aβ subtypes (Aβ40 and Aβ42) at low concentrations, promoting the formation of more Aβ oligomers and leading to evident neurotoxicity. The hydrophobic surface of PS facilitates the interaction of hydrophobic fragments between Aβ monomers, responsible for the augmented neurotoxicity. This work provides consequential insights into the modulatory impact of low-dose PS on Aβ aggregation and the ensuing neurotoxicity, presenting a valuable foundation for future research on the intricate interplay between environmental toxins and brain diseases.