Detection of Aβ Monomers and Oligomers: Early Diagnosis of Alzheimer's Disease

Alzheimer's disease (AD), as the most common progressive neurodegenerative disorder, is pathologically characterized by deposition of extracellular plaque composed of amyloid‐β peptide (Aβ). Different assembled states of Aβ have been considered as both important biomarkers and drug targets for the diagnosis and therapy of AD. Recent studies demonstrate that small, diffusible Aβ oligomers formed by aggregation of Aβ monomers are the major toxic agents in AD. Therefore, the development of reliable assays for Aβ (both monomers and oligomers) will be important for the early differential diagnosis of dementia, predicting the progression of AD, as well as monitoring the effectiveness of novel anti‐Aβ drugs for AD. In this review, we summarize the recent progress made in the development of techniques for detection of Aβ monomers and oligomers. In particular, the principles governing the design of these sensors are classified and summarized. Moreover, the advantages and disadvantages of the assays are evaluated. This review also discusses the improvements and challenges for application of these assays in the early diagnosis of AD.     

Biomarkers for Alzheimer's Disease – An Overview

Alzheimer's disease (AD) is a complex neurodegenerative disorder with a significant global impact on public health. The emergence of atypical clinical phenotypes challenges traditional diagnostic approaches, necessitating a deeper exploration of biomarkers for accurate identification. The US Food and Drug Administration (FDA) classification of biomarkers and their integration into different stages of AD provide a structured framework for their application in research and clinical settings. Within the context of AD drug development, biomarkers are essential for participant selection, target engagement evaluation, and assessment of pathological hallmarks, including Aβ and tau protein abnormalities. The incorporation of nanoparticles with a biodegradable approach introduces innovative strategies to address the complexities of AD. This paper extensively discusses biomarkers associated with synaptic dysfunction, neuroinflammation, and glial activation, recognizing their significance in elucidating disease mechanisms. Common pathologies such as synuclein and TDP-43 further underscore the multifaceted nature of AD. Current biomarkers for AD diagnosis, encompassing cerebral spinal fluid (CSF) biomarkers and various imaging modalities, reflect the ongoing efforts to enhance early detection and monitoring. Intriguingly, novel biomarkers continue to emerge, offering promising avenues for improved understanding and intervention. Current review provides a comprehensive survey of biomarkers for AD, elucidating their diverse roles across different aspects of the disease. By highlighting their contributions to diagnosis, drug development, and mechanistic insights, this overview underscores the importance of biomarker research in the pursuit of effective AD management and treatment strategies.     

Modified screen printed electrode for development of a highly sensitive label-free impedimetric immunosensor to detect amyloid beta peptides

Alzheimer's disease (AD) is a fatal neurodegenerative disease affecting approximately 26 million people world-wide, and the number is increasing as life expectancy increases. Since the only reliable diagnosis for the pathology is histochemical post-mortem examination, there is a rather urgent need for reliable, sensitive and quick detection techniques. Amyloid beta, being one of the established and widely accepted biomarkers of AD is a target biomolecule.     

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

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

Effect of Vacancy Defects on the Young's Modulus and Fracture Strength of Graphene: A Molecular Dynamics Study

The Young's modulus of graphene with various rectangular and circular vacancy defects is investigated by molecular dynamics simulation. By comparing with the results calculated from an effective spring model, it is demonstrated that the Young's modulus of graphene is largely correlated to the size of vacancy defects perpendicular to the stretching direction. And a linear reduction of Young's modulus with the increasing concentration of mono‐atomic‐vacancy defects (i.e., the slope of ?0.03) is also observed. The fracture behavior of graphene, including the fracture strength, crack initiation and propagation are then studied by the molecular dynamics simulation, the effective spring model, and the quantized fracture mechanics. The blunting effect of vacancy edges is demonstrated, and the characterized crack tip radius of 4.44 Å is observed.     

Detecting Alzheimer's disease biomarkers: From antibodies to new bio-mimetic receptors and their application to established and emerging bioanalytical platforms – A critical review

The failure of therapeutic treatment of Alzheimer's disease (AD) patients can be related to the late onset of symptoms and, consequently, to a delayed pharmacological aid to counteract neurodegenerative progression. This is coupled to the fact that the diagnosis based on clinical criteria alone introduces high misdiagnosis rate. The availability of assessed biomarkers is therefore of crucial importance not only to counteract late diagnosis, but also to manage patients at high risk of AD development eligible for novel therapies. At the present time, amyloid-β peptides (Aβ_1-40 and Aβ_1-42 isoforms), alone or in combination with Tau protein (total and phosphorylated forms (p-tau)) constitute reliable AD biomarkers and result highly predictive of progression to AD dementia in patients with mild cognitive impairment (MCI), the earliest clinical presentation of AD. Improvement of existing diagnostic tools must take advantage of innovative bioanalytical approaches. In this review, starting from commercially available diagnostic platforms based on antibodies as recognition elements, we intended to provide a double point of view on the issue: 1) progresses achieved on innovative bioanalytical platforms (mainly sensors and biosensors) by using antibodies as consolidated receptors; 2) advance on promising bio-mimetic receptors alternative to antibodies in AD research, and their applications on conventional or innovative analytical platforms. In particular, we first focused on optical- (Propagating and Localized Surface Plasmon Resonance, named here SPR and LSPR) and electrochemical (voltammetric and impedimetric) transduction principles. Together with bioanalytical assays for AD biomarkers quantification, works aimed to investigate and understand their behavior, characteristics, and roles will also be considered in the discussion.     

Advances in electrochemical detection for probing protein aggregation

Electrochemistry provides an array of methods to investigate protein aggregation and determine biomarkers of neurodenenerative diseases. Biosensors detecting monomeric or oligomeric biomarkers of Alzheimer's disease and Parkinson's disease evolved toward femtomolar, multiplexed detection in blood and biological fluids for less invasive diagnosis. The biosensors also serve as complementary tools in studies investigating putative biomarkers for the assessment of patient's cognitive decline. The study of protein aggregation via the direct electrochemical oxidation focused recently on enhanced sensitivity and on establishing correlations between protein structure and aggregation propensity. Departing from classic approaches, nanopore resistive pulse sensing and single-particle collision electrochemistry enable studying aggregates in solution. Growing applications converge toward accurate evaluation of aggregate populations and method adoption beyond proof of principle.     

基于质谱检测的相关色谱技术在阿尔茨海默病诊断中的应用

随着世界老年人口的急速增长,阿尔茨海默病发病人数也逐年增多,已成为继心脑血管疾病和恶性肿瘤之后威胁人类健康的“第三大杀手”。疾病的诊断和治疗同等重要,阿尔茨海默病诊断通常依靠典型的临床特征、神经影像技术以及检测疾病相关的生物标志物等。近些年来蛋白质组学和质谱技术迅速发展,可以利用这些技术寻找到与疾病相关的特异性的蛋白质分子作为早期诊断的生物标志物。本文就此进行了综述,主要包括基于蛋白质组学的诊断标志物的筛选和基于质谱检测的色谱技术在阿尔茨海默病诊断中的应用,引用文献34篇。     

Elastic modulus and thermal conductivity of ultradrawn polyethylene

The axial and transverse Young's modulus and thermal conductivity of gel and single crystal mat polyethylene with draw ratios λ = 1–350 have been measured from 160 to 360 K. The axial Young's modulus increases sharply with increasing λ, whereas the transverse modulus shows a slight decrease. The thermal conductivity exhibits a similar behavior. At λ = 350, the axial Young's modulus and thermal conductivity are, respectively, 20% and three times higher than those of steel. For this ultradrawn material both the magnitude and the temperature dependence of the axial Young's modulus are close to those of polyethylene crystal. The high values of the axial Young's modulus and thermal conductivity arise from the presence of a large percentage (∼85%) of long needle crystals. © 1999 John Wiley & Sons, Inc. J Polym Sci B: Polym Phys 37: 3359–3367, 1999     

Mechanical Properties of a Single Electrospun Fiber and Its Structures

Summary: A method to measure the Young's modulus of a single electrospun polyacrylonitrile (PAN) fiber is reported. The Young's modulus can be calculated from the force‐displacement curves obtained by the bending of a single fiber attached to an atomic force microscopy (AFM) cantilever. It is suggested that the high modulus of electrospun fibers is caused by the orientation of molecular chains, which is confirmed by wide‐angle X‐ray diffraction (WAXD) measurements. The communication will provide a basic understanding of the relationship between mechanical properties and structures of electrospun fibers.

A PAN fiber was attached to a contact mode cantilever to facilitate the measurement of force‐displacement curves and Young's modulus.     

Thermo-mechanical characterisation of in-plane properties for CSM E-glass epoxy polymer composite materials – Part 2: Young's modulus

The in-plane Young's modulus of a CSM E-glass/epoxy material is characterised through the use of dynamic mechanical analysis (DMA). The measured data is used to generate material models which describe the property behaviour as a function of conversion and temperature. Gelation of the epoxy resin plays a major role in the modulus development and is measured directly on the glass/epoxy material. The Young's modulus is described through a bi-functional model including the liquid/solid transition of the material. The evolution of Young's modulus is modelled by decoupling modulus increments caused by time and temperature, and is graphically illustrated through a Modulus-Temperature-Transformation (MTT) diagram. Based on the established material models presented in this paper and models in Part-1, it is feasible to assess residual stresses and shape distortions of composite parts made from this glass/epoxy material.     

Hardness and Young's modulus of transcrystalline polypropylene by Vickers and Knoop microindentation

A study of the anisotropic microhardness and Young's modulus of transcrystalline isotactic polypropylene grown from the surface of high modulus carbon fibers is described. Static microindentation experiments were performed with Knoop and Vickers tips. The Young's moduli of the transcrystalline region were estimated from Knoop microindentation data by using a method recently developed in our laboratory. Data for the different lamellar directions were generated using the Knoop tip, which is sensitive to material anisotropy. We found that the hardness and Young's modulus of the transcrystalline layer are higher by up to 30% when the longer diagonal of the probing Knoop tip is perpendicular to the transcrystalline growth direction, compared to when the diagonal is parallel to that direction. © 1999 John Wiley & Sons, Inc. J Polym Sci B: Polym Phys 37: 523–530, 1999     

Effects of humidity on Young's modulus in poly(methyl methacrylate)

Tensile tests on poly (methyl methacrylate) (PMMA) were conducted to clarify the effects of humidity and strain rate on tensile properties, particularly Young's modulus. Prior to the tensile tests, specimens were kept under various humidity conditions at 293 K, which were the same as the test conditions, for a few months to adjust the sorbed water content in the specimens. The tensile tests were performed under each humidity condition at three different strain rates (approximately 1.4 × 10^?3, 1.4 × 10^?4, and 1.4 × 10^?5 s^?1). Stress‐strain curves changed with humidity and strain rate. Young's moduli were also measured at small applied stresses (below 6.7 MPa) under various humidity conditions at 293 K. Young's modulus decreases linearly with increasing humidity and a decreasing logarithm of strain rate. These results suggest that Young's modulus of PMMA can be expressed as a function of two independent parameters that are humidity and strain rate. A constitutive equation for Young's modulus of PMMA was proposed. © 2002 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 40: 460–465, 2002; DOI 10.1002/polb.10107     

Estimation of frequency- and time-dependence of polymer composite system by viscoelasticity in three dimensions

This paper is concerned with the comparison between mechanical properties of polymer composite system and those of each individual constituent. The comparison is mainly performed with respect to the viscoelastic Young's modulus and the relaxation Young's modulus. These mechanical constants may be obtained from the correspondence principle by applying the Laplace transform to the constitutive equation. The calculated results exhibit that the mechanical property of polymer composite system strongly depends on that of matrix with respect to frequency- and time-dependences. That is, as for the vibration and dynamic response in the steady state, the frequency-dependence of peak position about imaginary part of dynamic modulus of composite system is similar to that of matrix, while the magnitude of dynamic modulus depends on volume fraction of dispersed particles to total volume. As for the stress relaxation, the time-dependence of the relaxation Young's modulus of composite system resemble that of matrix each other, while the magnitude depends on the volume fraction of dispersed particles to total volume. This is due to the calculating condition that particle is assumed to be very rigid in comparison with matrix in this paper.     

Stability of adsorber resins under mechanical compression and ultrasonication

Different adsorber and ion exchange resins have been sonicated with ultrasound of different frequencies in a fixed bed. Afterwards, the sonicated particles were investigated by scanning electron and light microscopy. Also, different mechanical properties, like fracture load, maximum flattening and Young's modulus were measured in compression tests and compared to the results of the ultrasonication experiments. Cavitational collapses cause cracks in resins with a high fracture load and a high Young's modulus as well as a low deformation at fracture. Complete destruction of adsorbent particles due to acoustic cavitation is observed with particles of low fracture loading and low Young's modulus. No or only little destruction is observed with particles which inhibit both sufficient strength and deformation properties. On the basis of these findings it is concluded that resin particles with optimum resistance to ultrasound show both a sufficient fracture load as well as high mechanical flexibility. Copyright © 2002 John Wiley & Sons, Ltd.     

Anisotropic elastic moduli and Poisson's ratios of a poly(ethylene terephthalate) film

Expressions for the directional dependence of Young's modulus and Poisson's ratio were derived for a general material under plane‐stress conditions. Experiments with a laser extensometer to measure the Young's modulus and Poisson's ratio directly by a tension test are described, and the results are compared with the theoretical expressions. © 2003 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 42: 260–266, 2004     

Effects of Specific Inhibitors for CaMK1D on a Primary Neuron Model for Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common cause of dementia worldwide. Despite extensive research and targeting of the main molecular components of the disease, beta-amyloid (Aβ) and tau, there are currently no treatments that alter the progression of the disease. Here, we examine the effects of two specific kinase inhibitors for calcium/calmodulin-dependent protein kinase type 1D (CaMK1D) on Aβ-mediated toxicity, using mouse primary cortical neurons. Tau hyperphosphorylation and cell death were used as AD indicators. These specific inhibitors were found to prevent Aβ induced tau hyperphosphorylation in culture, but were not able to protect cells from Aβ induced toxicity. While inhibitors were able to alter AD pathology in cell culture, they were insufficient to prevent cell death. With further research and development, these inhibitors could contribute to a multi-drug strategy to combat AD.     

UPLC-TOF MS-Based Metabonomic Study on Coadministration of Huperzine A and Ligustrazine Phosphate for Treatment of Alzheimer’s Disease

This work was designed to assess the holistic efficacy of concurrent treatment with huperzine A (HA) and ligustrazine phosphate (LP) in the animal model, and to interpret the metabonomics characteristics of the poly-therapy in treating Alzheimer’s disease (AD). Metabolic profiling of the brain was performed using ultra performance liquid chromatography coupled to time-of-flight mass spectroscopy (UPLC-TOF MS). Principal component analysis and partial least squares discriminant analysis were utilized to classify and reveal the differences among the control, model and treatment groups. Ten potential biomarkers have been finally gained. The metabonomic results revealed that the coadministration of HA and LP might slow down the progression of AD through synergistic therapeutic efficacies, exhibiting better effect on amnesia compared with the mono-drug therapy. Importantly, the UPLC-TOF MS-based metabonomic approach would be a useful technique for the diagnosis of AD, the discovery of metabolic biomarkers and the evaluation of the treatment effects.

     

Synthesis and Characterization of Polyester-Based Nanocomposite

Recently, unsaturated polyester resin (UPR) and silica nanocomposite prepared by mechanical process is the one of the promising composite materials. In this study, the effects of silica as filler on mechanical, thermal, and morphological properties of unsaturated polyester-based composite were investigated. Mechanical properties such as tensile strength, elongation and Young's modulus increase with the addition of silica nanoparticle up to 1.0 wt%, and then decrease, over 1.0 wt%. Morphological surface of composite reveals that well-dispersed silica in the matrix occurred in low concentration. However, increasing of silica concentration causes aggregation of particles. Enhancement of mechanical properties strongly corresponds to strong adhession force of silica with the matrix and it influnced by well-disperse silica particles on the whole surface of composite. Thermal characterization and analysis of major functional group of the composites were also performed and described in this paper.     

In Silico Analysis of Metabolites from Peruvian Native Plants as Potential Therapeutics against Alzheimer’s Disease

Background: Despite research on the molecular bases of Alzheimer’s disease (AD), effective therapies against its progression are still needed. Recent studies have shown direct links between AD progression and neurovascular dysfunction, highlighting it as a potential target for new therapeutics development. In this work, we screened and evaluated the inhibitory effect of natural compounds from native Peruvian plants against tau protein, amyloid beta, and angiotensin II type 1 receptor (AT1R) pathologic AD markers. Methods: We applied in silico analysis, such as virtual screening, molecular docking, molecular dynamics simulation (MD), and MM/GBSA estimation, to identify metabolites from Peruvian plants with inhibitory properties, and compared them to nicotinamide, telmisartan, and grapeseed extract drugs in clinical trials. Results: Our results demonstrated the increased bioactivity of three plants’ metabolites against tau protein, amyloid beta, and AT1R. The MD simulations indicated the stability of the AT1R:floribundic acid, amyloid beta:rutin, and tau:brassicasterol systems. A polypharmaceutical potential was observed for rutin due to its high affinity to AT1R, amyloid beta, and tau. The metabolite floribundic acid showed bioactivity against the AT1R and tau, and the metabolite brassicasterol showed bioactivity against the amyloid beta and tau. Conclusions: This study has identified molecules from native Peruvian plants that have the potential to bind three pathologic markers of AD.