Beta Peptide Research Articles

Circulating levels of amyloid-beta (1-40) peptide associate with cardiometabolic traits and risk for metabolic dysfunction-associated steatotic liver disease

Abstract Background and Aims The ageing-associated amyloid-beta 1-40 peptide (Αbeta40) has recently emerged as a blood-based biomarker of cardiovascular disease (CVD). Its levels predict future cardiovascular death and MACE in patients with established CVD. The clinical value of Abeta40 in patients with metabolic syndrome who do not concomitantly have clinically overt CVD or other end-organ damage remains poorly understood. At the present study we investigated the clinical value of plasma Αbeta40 in patients with pre- or established metabolic syndrome who are at risk for metabolic dysfunction-associated steatotic liver disease (MASLD). Methods Αbeta40 was measured in plasma by enzyme-linked immunosorbent assay and cardiometabolic traits were determined in a mixed population (n=888) of patients with established (n=243) and pre- or without metabolic syndrome (n=645) who did not have clinical signs of established cardiometabolic disease (heart failure, coronary artery disease, MASLD, chronic kidney disease). The endpoint of the study was the association of Abeta40 with cardiometabolic indices and risk (BARD score) for MASLD. Odds ratio (OR) was calculated by ordinal regression analysis for the increasing incidence of metabolic syndrome components per increasing Abeta40 (1-SD) after adjustment for age, sex, smoking status and hyperlipidemia. Results Abeta40 levels are associated with the presence of metabolic syndrome and with higher odds for increasing incidence of metabolic syndrome components after adjustment for sex, age, smoking status, hypertension and dyslipidemia. Increased Abeta40 plasma levels were associated with decreased HDL-C levels (OR: 1.004, 95% CI:1.000-1.009, P=0.049) and increased triglyceride levels (OR: 1.007, 95%CI: 1.001-1.012, P=0.033) after adjustment for traditional cardiovascular risk factors (age, sex, smoking status, hypertension and hyperlipidemia). Among the total population (n=888), we identified n=473 subjects with increased MASLD risk if any of the following was present: hepatic steatosis index≥36 or fatty liver index≥60 or Fib-4 index≥2.67 or NAFLD score≥0.675. Among patients with high-risk for MASLD, patients with increased BARD score had significantly higher Abeta40 levels (median Abeta40 concentration in patients with BARD score≥2 vs. patients with BARD score<2: 54.9 pg/ml (IQR=38.25) vs. 41.9 pg/m (IQR=30.35), P=0.012). Increased Abeta40 levels were associated with increased odds for AST/ALT≥0.8 ratio and increased odds for BARD score≥2 after adjustment for age, sex, smoking status, hypertension and hyperlipidemia. Conclusion Our findings suggest that Abeta40 peptide is associated with cardiometabolic traits and risk for MASLD. Whether Abeta40 may emerge as an early cardiometabolic prognostic biomarker, future longitudinal studies are warranted to determine the prognostic value of Abeta40 for the development of cardiometabolic diseases in patients with metabolic syndrome.

Brazilian kefir fraction mitigates the Alzheimer-like phenotype in Drosophila melanogaster with β-amyloid overexpression model

Alzheimer’s disease (AD) is a progressive neurodegenerative condition and the primary form of dementia among elderly people. The amyloidogenic hypothesis is the main theory that explains this phenomenon and describes the extracellular accumulation of amyloid beta (Aβ) peptides. Model organisms such as Drosophila melanogaster have been utilized to improve the understanding of this disease and its treatment. This study evaluated the effects of peptide and metabolic fractions of Brazilian kefir on a strain of D. melanogaster that expresses human Aβ peptide 1–42 in the eye. The parameters assessed included ommatidial organization, vacuole area, retinal thickness, and Aβ peptide quantification. The present study revealed that the fractions, particularly the peptidic fraction, significantly reduced the vacuole area and increased the retina thickness in treated flies, indicating an improvement in neurodegeneration phenotype. The peptidic fraction was also found to alter Aβ aggregation dynamics, inhibiting Aβ fibril formation, as revealed by dynamic light scattering. This study demonstrated that kefir fractions, particularly the peptidic fraction < 10 kDa, have the potential to regulate Aβ aggregation and alleviate neurodegeneration in a Drosophila melanogaster AD-like model. These findings suggest that kefir fractions could be viable for the bioprospection of novel drug prototypes for AD treatment, providing valuable insights into strategies targeting Aβ aggregation and neurodegeneration in AD.

Molecular mechanisms underlying amyloid beta peptide mediated upregulation of vascular cell adhesion molecule-1 in Alzheimer's disease.

Amyloid beta (Aβ) deposition and neurofibrillary tangles are widely considered as the primary pathological hallmarks of familial and sporadic forms of Alzheimer's disease (AD). However, cerebrovascular inflammation, which is prevalent in 70% of AD patients is emerging as another core feature of AD pathology. In addition, activation of inflammatory signaling pathways have been observed in AD patients; specifically, cerebrovascular inflammation was found to be augmented in Alzheimer's patients. Our studies have demonstrated that the inflammation signaling pathway is upregulated in AD patient brains. Moreover, vascular cell adhesion molecule-1 (VCAM-1), a cerebrovascular inflammatory marker expressed on the blood-brain barrier (BBB) endothelium, was observed to be upregulated in APP,PS1 mice (a mouse model that overexpresses Ab42), as detected by dynamic SPEC/CT imaging. While there is a strong association between Aβ42 exposure and an increase in VCAM-1 expression, the mechanisms underlying the influence of Aβ42 on VCAM-1 expression remain understudied. Therefore, we investigated the hypothesis that Ab42 exposure increases VCAM-1 expression in human cerebral microvascular endothelial cell (hCMEC/D3) monolayers. In addition, reverse phase protein array assays (RPPA) and immunocytochemistry demonstrated that Ab42 increases VCAM-1 expression through the Src/p38/MEK signaling pathway specifically within the blood-brain barrier (BBB) endothelium. In summary, these results demonstrate that Ab42 augments cerebrovascular inflammation by elevating VCAM-1 expression via Src/MEK/p38 pathway. Hence, targeting VCAM-1 at the BBB as a diagnostic and therapeutic marker may hold potential for detecting and mitigating cerebrovascular inflammation in Alzheimer's disease. Significance Statement While considered a core pathological feature of Alzheimer's disease, molecular pathways leading to cerebrovascular inflammation remain partially understood. Moreover, clinical diagnostic methods for detecting cerebrovascular inflammation are underdeveloped. In this study, we demonstrated VCAM-1 detection using radio-iodinated VCAM-1 antibody and SPECT/CT imaging. The study demonstrated that the exposure to Aβ42 increases VCAM-1 expression on the BBB endothelium via Src/p38/MEK pathway. These findings are expected to aid in the development of diagnostic and therapeutic approaches for addressing cerebrovascular inflammation in AD.

Effects of Angiotensin-I-Converting Enzyme (ACE) Mutations Associated with Alzheimer's Disease on Blood ACE Phenotype.

Our recent analysis of 1200+ existing missense ACE mutations revealed that 400+ mutations are damaging and led us to hypothesize that carriers of heterozygous loss-of-function (LoF) ACE mutations (which result in low ACE levels) could be at risk for the development of late-onset Alzheimer's disease (AD). Here, we quantified blood ACE levels in EDTA plasma from 41 subjects with 10 different heterozygous ACE mutations, as well as 33 controls, and estimated the effect of these mutations on ACE phenotype using a set of mAbs to ACE and two ACE substrates. We found that relatively frequent (~1%) AD-associated ACE mutations in the N domain of ACE, Y215C, and G325R are truly damaging and likely transport-deficient, with the ACE levels in plasma at only ~50% of controls. Another AD-associated ACE mutation, R1250Q, in the cytoplasmic tail, did not cause a decrease in ACE and likely did not affect surface ACE expression. We have also developed a method to identify patients with anti-catalytic mutations in the N domain. These mutations may result in reduced degradation of amyloid beta peptide Aβ42, an important component for amyloid deposition. Consequently, these could pose a risk factor for the development of AD. Therefore, a systematic analysis of blood ACE levels in patients with all ACE mutations has the potential to identify individuals at an increased risk of late-onset AD. These individuals may benefit from future preventive or therapeutic interventions involving a combination of chemical and pharmacological chaperones, as well as proteasome inhibitors, aiming to enhance ACE protein traffic. This approach has been previously demonstrated in our cell model of the transport-deficient ACE mutation Q1069R.

CSF and blood levels of Neurofilaments, T-Tau, P-Tau, and Abeta-42 in amyotrophic lateral sclerosis: a systematic review and meta-analysis.

Recent literature suggests that markers of neuroaxonal damage, such as neurofilaments and tau protein, might serve as potential biomarkers for ALS. We conducted this systematic review and meta-analysis study to compare cerebrospinal fluid (CSF) and blood levels of total tau (t-tau), phosphorylated tau (p-tau), amyloid beta peptide 42 (Abeta-42), and neurofilaments in ALS patients and controls. A systematic search of Cochrane Library, PubMed, Embase, and ISI Web of Science was conducted on March 18, 2022, and updated on January 26, 2023. Observational studies that compared the concentrations of neurofilament light chain (NfL), neurofilament heavy chain (NFH), t-tau, p-tau, or Abeta-42 in CSF or peripheral blood of ALS patients and controls were included. Data from relevant studies were independently extracted and screened for quality using a standard tool, by at least two authors. Meta-analysis was conducted when a minimum of 3 studies reported the same biomarker within the same biofluid. A total of 100 studies were eligible for at least one meta-analysis. CSF and blood levels of NfL (standardized mean difference (SMD) [95% CI]; CSF: 1.46 [1.25-1.68]; blood: 1.35 [1.09-1.60]) and NFH (CSF: 1.32 [1.13-1.50], blood: 0.90 [0.58-1.22]) were significantly higher in ALS patients compared with controls. The pooled differences between ALS patients and controls were not significant for CSF t-tau, blood t-tau, and CSF Abeta-42, but CSF p-tau was lower in ALS patients (-0.27 [-0.47- -0.07]). Significantly decreased p-tau/t-tau ratios were found in ALS patients compared with controls (-0.84 [-1.16- -0.53]). Heterogeneity was considerable in most of our meta-analyses. CSF and blood neurofilament levels, as well as the CSF p-tau/t-tau ratio, might be potential candidates for improving ALS diagnosis. Further research is warranted to better understand the underlying mechanisms and the clinical implications of these biomarker alterations.

Tyrosine modifications of insulin-degrading enzyme enable favorable control of substrate specificity for both Alzheimer’s disease and type-2 diabetes mellitus

Insulin-degrading enzyme (IDE) cleaves amyloid beta (Aβ), insulin, and other bioactive peptides. Because Aβ and insulin are closely related to Alzheimer’s disease (AD) and type-2 diabetes mellitus (T2DM), respectively, IDE is a candidate drug target for treating both AD and T2DM. However, the activity of IDE has opposing effects, including decreasing AD risk by degrading Aβ and increasing T2DM risk by degrading insulin. The opposed substrate specificity is associated with the exo- and active sites containing Tyr314 and Tyr831 residues, the plausible modification targets for controlling substrate specificity. In this study, we used a tyrosine-specific modification regent, Cookson reagent (4-phenyl-1,2,4-triazoline-3,5-dione, PTAD), for IDE and examined the degradation activities on Aβ40 and insulin. Fifteen tyrosine residues, including Tyr314 and Tyr831, were modified by PTAD. After incubation with PTAD-modified IDE for 3 days, insulin remained intact, whereas Aβ40 was completely degraded. This favorable change of substrate specificity was also observed in the mixture of Aβ40 and insulin, suggesting that tyrosine modification of IDE might be a therapeutic strategy for AD and T2DM.

Synthesis and Evaluation of amyloid beta peptide/ Ruthenium III -based complex drugs as drug delivery and anticancer activity

The development and characterization of anticancer complex drugs (ACD), specifically Amyloid Beta Peptide (ABP) - Ruthenium III (Ru III) - nivolumab (NB), were explored through analytical techniques. Fourier-transform infrared (FTIR) spectroscopy demonstrated the structural transformation of peptides from α-helical to β-sheet formations, aligning with amyloid fibril aggregation. Ruthenium (III) complex synthesis was confirmed through distinct absorption peaks in FTIR analysis. High-resolution scanning electron microscopy (HRSEM) revealed the fibrous and smooth morphology of ACD, while thermogravimetric analysis (TGA) confirmed the decomposition stages and stability of the ruthenium complexes. The encapsulation efficiency and in vitro release profile of nivolumab (NB) within ABP-RuIII-NB were investigated, showing a two-phase release over 40h. Cytotoxicity studies using acridine orange and ethidium bromide staining techniques indicated significant apoptosis in human oral squamous cell carcinoma (OSCC) -treated cells. These findings highlight the potential of ABP-RuIII-NB as an effective cancer treatment with controlled drug release and high cytotoxicity against cancer cells.

Unlocking choline's potential in Alzheimer's disease: A narrative review exploring the neuroprotective and neurotrophic role of phosphatidylcholine and assessing its impact on memory and learning

Background and aimsGrowing evidence suggests nutritional intervention may influence the development and progression of Alzheimer‘s Disease (AD). Choline, an essential dietary nutrient plays a critical role in neurological development and brain function, however, its effects on AD in humans is unclear. The research aims to investigate mechanistic links between dietary choline intake and cognitive functioning, focusing on the role of phosphatidylcholine (PC) in neuroplasticity and its interaction with amyloid beta (Aβ) peptides in neuron membranes. Additionally, human evidence on potential benefits of PC interventions on AD, cognition and proposed mechanisms are evaluated. MethodsA reproducible systematic literature search was performed using a three-tranche strategy, consisting of a review, mechanism and intervention search. Using PubMed as the main database, 1254 titles and abstracts were screened, 149 papers were read in full and 65 peer-reviewed papers were accepted, critically appraised and analysed in a narrative review. ResultsPredominantly preclinical evidence demonstrated that PC enhances neuroplasticity, a key biological substrate for cognition, by activating intracellular neuronal signalling pathways or through neuron membrane function.Molecular dynamic simulation methods provided mechanistic understanding of the interconnection between neuronal PC content and the potential behaviour and trajectory of Aβ peptide aggregation. The results indicate that the neuronal membrane composition of PC is critical to inhibiting Aβ aggregation and neuronal damage, protecting the neuron from Aβ toxicity. This might provide a foundation for optimising cellular PC which may prove beneficial in the treatment or prevention of neurodegenerative disease.Altered PC metabolism in AD was evidenced in observational studies; however, whether this relationship represents a cause or consequence of AD remains to be determined. Human intervention studies did not produce conclusive evidence supporting its effectiveness in enhancing cognitive function. This lack of consistency primarily stems from methodological constraints within the conducted studies. Human observational research provided the most compelling evidence linking a higher dietary PC intake to reduced risk of dementia and significant improvements in cognitive testing. ConclusionDespite the lack of randomised control trials (RCTs) assessing the efficacy of lecithin/PC to improve cognition in AD patients, there exists promising evidence supporting its neuroprotective and neurotrophic role.This review establishes an evidence-based framework through chains of mechanistic evidence, that may provide potential strategies for enhanced neuroprotection and reduced neurodegeneration caused by AD. Considering the escalating global burden of AD and the current shortcomings in effective treatments, this review together with the limitations and gaps identified in the existing research present valuable insights that emphasise the urgency of more comprehensive research into the relationship between PC and AD.

Investigating Anion Effects on Metal Ion Binding Interactions With Amyloid β Peptide by Ion Mobility Mass Spectrometry.

The study of metal ion's role in the biological processes of Alzheimer's disease has spurred investigations into the coordination chemistry of amyloid beta peptide and its fragments. Nano-electrospray ionization mass spectrometry (nESI-MS) has been utilized to examine the stabilization of bound anions on multiprotein complexes without bulk solvent. However, the effects of anions on metal ion binding interactions with amyloid beta peptide have not been explored. This study directly examined metal-peptide complexes using nESI-MS and investigated the effects of various anions on the binding ratio and stability of these complexes from ammonium salt solutions. The results indicate that different anions have distinct effects on the binding ratio and stability of various metal-peptide complexes. Of these, the bicarbonate ion exhibits the highest binding ratios for metal-peptide complexes, while binding ratios for these complexes in phosphate are comparatively low. Our results suggest that acetate, formate, bicarbonate, and phosphate have weak affinities and act as weak stabilizers of the metal-peptide complex structure in the gas phase. Intriguingly, chloride and sulfate act as stabilizers of the metal-peptide complex in the gas phase. The rank order determined from these data is substantially different from the Hofmeister salt series in solution. Although this outcome was anticipated due to the reduced influence of anions and water solvation, our findings correlate well with expected anion binding in solution and emphasize the importance of both hydration layer and anion-metal-peptide binding effects for Hofmeister-type stabilization in solution. This approach proved useful in examining the interactions between metal ions and amyloid beta peptide, which are relevant to Alzheimer's disease, using direct ESI-MS.

MEDI1814 selectively reduces free Aβ42 in cerebrospinal fluid of non-clinical species and Alzheimer's disease patients.

Small molecules and antibodies are being developed to lower amyloid beta (Aβ) peptides. We describe MEDI1814, a fully human high-affinity monoclonal antibody selective for Aβ42, the pathogenic self-aggregating species of Aβ. MEDI1814 reduces free Aβ42 without impacting Aβ40 in the cerebrospinal fluid of rats and cynomolgus monkeys after systemic administration. MEDI1814 administration to patients with Alzheimer's disease (AD; n=57) in single or repeat doses up to 1800mg intravenously or 200mg subcutaneously was associated with a favorable safety and tolerability profile. No cases of amyloid-related imaging abnormalities were observed. Predictable dose-proportional changes in serum exposures for MEDI1814 were observed across cohorts. Cerebrospinal fluid (CSF) analysis demonstrated central nervous system penetration of MEDI1814. Pharmacodynamic data showed dose-dependent suppression of free Aβ42, increases in total (bound and free) Aβ42, but no change in total Aβ40 in CSF across doses. MEDI1814 offers a differentiated approach to impacting Aβ in AD via selective reduction of free Aβ42.

Structure-Activity Relationship of Fluorinated Benzenesulfonamides as Inhibitors of Amyloid-β Aggregation.

Amyloid-beta aggregation is considered one of the factors influencing the onset of the Alzheimer's disease. Early prevention of such aggregation should alleviate disease condition by applying small molecule compounds that shift the aggregation equilibrium toward the soluble form of the peptide or slow down the process. We have discovered that fluorinated benzenesulfonamides of particular structure slowed the amyloid-beta peptide aggregation process by more than three-fold. We synthesized a series of ortho-para and meta-para double-substituted fluorinated benzenesulfonamides that inhibited the aggregation process to a variable extent yielding a detailed picture of the structure-activity relationship. Analysis of compound chemical structure effect on aggregation in artificial cerebrospinal fluid showed the necessity to arrange the benzenesulfonamide, hydrophobic substituent, and benzoic acid in a particular way. The amyloid beta peptide aggregate fibril structures varied in cross-sectional height depending on the applied inhibitor indicating the formation of a complex with the compound. Application of selected inhibitors increased the survivability of cells affected by the amyloid beta peptide. Such compounds may be developed as drugs against Alzheimer's disease.

Microbiome to dictate the occurrence of neurological disorders

Neuropsychiatric disorders have been the constant burden impacting healthcare since 1990, and more than 3 billion people worldwide are living with neurological conditions. Mental health conditions with cognitive decline were also observed in people who contracted SARSCoV-2 and later presented the PACS related disease after the resolution of primary infection. Long term dysbiosis, inflammatory bowel disease (IBD), and neurological inflammations signify the establishment of major depressive disorders (MDD), Alzheimer’s disease (AD), Schizophrenia, Parkinson’s disease (PD), lateral sclerosis etc. More than 4% of cases of periodontitis are likely to develop brain related abnormalities. Conversely, cellular and molecular alterations keep restoring Amyloid beta peptides (Aβ), tau protein, and 2-synuclein protein with plaque formation allow the disease associate microglia (DAM TREM) phenotype to transfer the aberrant signals through post synaptic neurons. Brain related inflammations are accompanied by various agonist molecules, Lipopolysaccharides (LPS), increased C-reactive protein, tumor necrosis factor alpha (TNF-α), and mitochondrial dysfunctions. Firmicutes with Lactobacillus spp., Ruminococcus spp., Lachnospira spp. are the known short-chain fatty acids (SCFAs) producers, those meant to involve in regulating the immunological and physiological functions from Gut-Brain-Gut building homeostasis. Aβ stimulation of glial cells produces anti-inflammatory effects, while controlling the ERK/MAPK/JAK/NFkβ pathways-based inflammations. Serotonin, dopamine, gamma aminobutyric acid (GABA), kynurenic acid are the regulatory neurotransmitters that contribute to the prognosis of neurodegenerative diseases and also reduce the stress related corticosterone. Impaired molecular signals disrupt the endothelial layer of gut and blood brain barrier (BBB) impacting the serotonin production in brain. It is imperative to utilize pre, pro, and postbiotics to modulate the depleted microbiota, could reverse the aberrant signals instigating a better disease prognosis.

In 2024, the amyloid-cascade-hypothesis still remains a working hypothesis, no less but certainly no more.

The amyloid-cascade-hypothesis of the pathogenesis of Alzheimer's disease (AD) was introduced 32 years ago, in 1992. From early on, this clear and straight forward hypothesis received a lot of attention, but also a lot of substantial criticism. Foremost, there have always been massive doubts that a complex age-associated disorder of the most intricate organ of the human body, the brain, can be explained by a linear, one-dimensional cause-and-effect model. The amyloid-cascade defines the generation, aggregation, and deposition of the amyloid beta peptide as the central pathogenic mechanism in AD, as the ultimate trigger of the disease, and, consequently, as the key pharmacological target. Certainly, the original 1992 version of this hypothesis has been refined by various means, and the 'formulating fathers' followed up with a few reappraisals and partly very open reflections in 2002, 2006, 2009, and 2016. However, up until today, for the supporters of this hypothesis, the central and initial steps of the cascade are believed to be driven by amyloid beta-even if now displayed somewhat more elaborate. In light of the recently published clinical results achieved with anti-amyloid antibodies, the controversy in the field about (1) the clinical meaningfulness of this approach, (2) the significance of clearance of the amyloid beta peptide, and last but not least (3) the relevance of the amyloid-cascade-hypothesis is gaining momentum. This review addresses the interesting manifestation of the amyloid-cascade-hypothesis as well as its ups and downs over the decades.

Abstract P233: Amyloid Beta Plaque Deposits Co-Localize with Endothelial Cells in the Hippocampus of Female APPswe/PSEN1dE9 Mice During the Onset of Amyloid Pathology

Increasing evidence shows that cardiovascular diseases are associated with an increased risk of cognitive impairment and Alzheimer’s diseases (AD). It is unknown whether systemic vascular dysfunction occurs prior to the development of AD, if this occurs in a sex-dependent manner, or whether endothelial cells play a role in the deposition of amyloid beta (Aβ) peptides. We hypothesized that female mice present with an exacerbated formation of Aβ peptides, and vascular dysfunction would occur during the onset of amyloid pathology, thus escalating its progression. To test this hypothesis, we used a double transgenic mouse model of early onset AD (APPswe/PSEN1dE9) prior to the onset of amyloid pathology (3 months of age) and during the onset of amyloid pathology (7 months of age). Immunofluorescence was performed in the hippocampus stained with Aβ 1-42 and CD31 antibodies. High resolution images were acquired on the confocal microscope. Acetylcholine-induced relaxation (1pM-30µM) was evaluated in mesenteric resistance arteries (MRA), and the data analyzed as non-linear curve regression and maximum effect (Emax). The statistical analysis was performed using Student’s t test, or two-way ANOVA followed by Tukey post-hoc ( p &lt;0.05*). We observed that during the onset of amyloid pathology (7-months-old), there was elevated Aβ deposition which co-localized with endothelial cells in the hippocampus from female but not male APP/PS1 mice [females colocalization rate (%): control 12.9 ± 2.0 vs . APP/PS1 25.1 ± 7.8, n=4; males colocalization rate (%): control 23.2 ± 6.5 vs. APP/PS1 15.3 ± 3.3, n=4]. In addition, the 7-month-old female APP/PS1 mice showed an exacerbated endothelium-dependent relaxation compared to the 3-month-old group (female APP/PS1 7-month-old ACh Emax: 97.1 ± 1.6*%, n=4 vs. 3-month-old ACh Emax: 70.1 ± 8.3%, n=6). Furthermore, endothelial dysfunction occurred prior to the onset of amyloid pathology irrespective of sex. Overall, these data showed that the endothelial dysfunction prior to the onset of amyloid pathology may be an early marker of AD. Further, a greater burden of Aβ formation in hippocampal endothelial cells from female but not male APP/PS1 mice may be associated with vascular abnormalities and dysfunction.

Hop leaves: From waste to a valuable source of bioactive compounds – A multidisciplinary approach to investigating potential applications

After harvesting of cones used for beer production, the remaining hop vegetative biomass requires disposal. The hop plant contains bioactive compounds in all its parts—cones, leaves, and roots—exhibiting interesting antioxidant, antiviral, and antibacterial properties. In this work, extracts obtained from hop leaves, a plant material often neglected in the hop cultivation, have been investigated; the qualitative UHPLC-MS/MS and GC-TOF-MS characterization revealed the presence of bioactive compounds such as polyphenols, α- and β-acids and terpenes are present. The extract retained antioxidant activity, as verified by Folin-Ciocalteu, DPPH, ABTS and FRAP assays, and demonstrated some antimicrobial activity when combined with antibiotics, particularly against Gram-positive bacterial strains. Additionally, the extracts showed an ability to interact with proteins as human insulin, amyloid beta peptide, mucin and bovine serum albumin (BSA), has been detected, indicating their potential to counteract inflammatory processes and protect against Alzheimer's disease. These findings suggest that hop vegetative biomass, typically considered waste, can be potentially transformed into a valuable resource with applications in various fields, from nutraceuticals to pharmaceuticals and cosmetics, aligning with a circular economy perspective.

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.

HSP110 is a modulator of amyloid beta (Aβ) aggregation and proteotoxicity.

Chaperones safeguard protein homeostasis by promoting folding and preventing aggregation. HSP110 is a cytosolic chaperone that functions as a nucleotide exchange factor for the HSP70 cycle. Together with HSP70 and a J-domain protein (JDP), HSP110 maintains protein folding and resolubilizes aggregates. Interestingly, HSP110 is vital for the HSP70/110/JDP-mediated disaggregation of amyloidogenic proteins implicated in neurodegenerative diseases (i.e., α-synuclein, HTT, and tau). However, despite its abundance, HSP110 remains still an enigmatic chaperone, and its functional spectrum is not very well understood. Of note, the disaggregation activity of neurodegenerative disease-associated amyloid fibrils showed both beneficial and detrimental outcomes invivo. To gain a more comprehensive understanding of the chaperone HSP110 invivo, we analyzed its role in neuronal proteostasis and neurodegeneration in C. elegans. Specifically, we investigated the role of HSP110 in the regulation of amyloid beta peptide (Aβ) aggregation using an established Aβ-C. elegans model that mimics Alzheimer's disease pathology. We generated a novel C. elegans model that over-expresses hsp-110pan-neuronally, and we also depleted hsp-110 by RNAi-mediated knockdown. We assessed Aβ aggregation invivo and insitu by fluorescence lifetime imaging. We found that hsp-110 over-expression exacerbated Aβ aggregation and appeared to reduce the conformational variability of the Aβ aggregates, whereas hsp-110 depletion reduced aggregation more significantly in the IL2 neurons, which marked the onset of Aβ aggregation. HSP-110 also plays a central role in growth and fertility as its over-expression compromises nematode physiology. In addition, we found that HSP-110 modulation affects the autophagy pathway. While hsp-110 over-expression impairs the autophagic flux, a depletion enhances it. Thus, HSP-110 regulates multiple nodes of the proteostasis network to control amyloid protein aggregation, disaggregation, and autophagic clearance.

Neuroprotective effects of resveratrol through modulation of PI3K/Akt/GSK-3β pathway and metalloproteases.

To analyze the expressional changes in the PI3K/Akt/GSK-3β pathway and metalloprotease in the cellular Alzheimer's Disease (AD) model with the effect of antioxidant resveratrol. Neuron-like cells were obtained by a two-step method of neuronal differentiation by using a combination of retinoic acid (RA) and brain-derived factor (BDNF) exposure. Then, the application of the amyloid beta peptide 25-35 (Aβ25-35) to the cell culture mimicked the environmental toxicity observed in AD. Afterward, cell viability and apoptosis assays were performed to determine whether the resveratrol exerts a cytotoxic and apoptotic effect. Finally, the expressional changes in genes in the cellular AD model with the effect of resveratrol were analyzed by Real-Time PCR. The analysis in silico was assessed using the STRING V12.0 database in each group. Apoptosis data findings were decreased by 1.5-fold and 2.5-fold respectively by Differentiated+Resveratrol (RES) and RES when compared to control but no significant difference was observed between RES and AD model groups. Real-time PCR analysis results revealed PI3K (3.38-fold), AKT (3.95-fold), and RELN (1.99-fold) expressions were significantly higher (p < .001), and also GSK-3β, TAU, ADAMTS-4, ADAMTS-5, and TIMP-3 gene expression levels were significantly downregulated (2.53-, 1.79-, 2.85-, 4.09-, and 6.62-fold, respectively) in the Differentiated+Aβ + RES groups compared to the Differentiated+Aβ group (p < .001). Network analysis shows the functional enrichment of 23 Alzheimer-related GO terms in the Wnt signaling, proteolysis, and extracellular matrix organization pathways. Resveratrol has inhibited GSK-3β by activating the PI3K/Akt insulin pathway in a neurotoxic environment. In addition, TAU, RELN, metalloproteases, and their inhibitors associated with Alzheimer's pathology have been regulated supporting the neuroprotective effect of resveratrol.

Self-assembled low molecular weight chitosan-bilobalide microsuspension protects hippocampal toxicity in amyloid beta(25–35) induced mice

Alzheimer's disease (AD) is a progressive neurological disorder and is characterized by the accumulation of amyloid beta (Aβ) peptide and hyperphosphorylated tau as a pathological hallmark. Bilobalide (BB) being a highly hydrophobic compound, has poor aqueous solubility, stability, and brain bioavailability. In the present study, we prepared self-assembled low molecular weight chitosan-bilobalide microsuspension (BBC) and examined its neuroprotective effect against intracerebroventricular induction of Aβ(25–35) toxicity in mice. Results showed that BBC has a particle size of 5.77 µm with a desired zeta potential of +42.2 ± 2 mV. BBC displayed aqueous solubility with sustained release kinetics in vitro and had better intracellular transport (70 %) of BB from BBC in Caco-2 cells. Further, treatment with BBC showed increased content [BBC (10 mg), 83.4 ng; BB (10 mg), 15.8 ng] of BB in brain and alleviated Aβ(25–35) induced memory impairment in mice. Moreover, BBC diminished oxidative stress, neuroinflammation, and synaptic dysfunction in Aβ(25–35) induced AD model. In addition, our western blot data suggested that treatment with BBC ameliorated Aβ(25–35) induced hyperphosphorylation of tau protein through regulation of aberrant phosphorylation of Akt/GSK3β/MAPK pathway. The current study may confirm the application of BBC as an oral supplement in the food and pharmaceutical industries for AD conditions.

Aggregation Dynamics of a 150 kDa Aβ42 Oligomer: Insights from Cryo Electron Microscopy and Multimodal Analysis.

I.Protein misfolding is a widespread phenomenon that can result in the formation of protein aggregates, which are markers of various disease states, including Alzheimer's disease (AD). In AD, amyloid beta (Aβ) peptides, particularly Aβ40 and Aβ42, are key players in the disease's progression, as they aggregate to form amyloid plaques and contribute to neuronal toxicity. Recent research has shifted attention from solely Aβ fibrils to also include Aβ protofibrils and oligomers as potentially critical pathogenic agents. Particularly, oligomers demonstrate greater toxicity compared to other Aβ specie. Hence, there is an increased interest in studying the correlation between toxicity and their structure and aggregation pathway. The present study investigates the aggregation of a 150 kDa Aβ42 oligomer that does not lead to fibril formation over time. Using negative stain transmission electron microscopy (TEM), size exclusion chromatography (SEC), dynamic light scattering (DLS), and cryo-electron microscopy (cryo-EM), we demonstrate that 150 kDa Aβ42 oligomers form higher-order string-like assemblies over time. The strings are unique from the classical Aβ fibril structures. The significance of our work lies in elucidating molecular behavior of a novel non-fibrillar form of Aβ42 aggregate.