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Alzheimer's disease (AD) is the most common neurodegenerative condition in civilizations worldwide. The distinctive occurrence of amyloid-beta (Aβ) accumulation into insoluble fibrils is part of the disease pathophysiology with Aβ42 being the most toxic and aggressive Aβ species. The polyphenol, p -Coumaric acid (p CA), has been known to boost a number of therapeutic benefits. Here, p CA's potential to counteract the negative effects of Aβ42 was investigated. First, p CA was confirmed to reduce Aβ42 fibrillation using an in vitro activity assay. The compound was next examined on Aβ42-exposed PC12 neuronal cells and was found to significantly decrease Aβ42-induced cell mortality. p CA was then examined using an AD Drosophila melanogaster model. Feeding of p CA partially reversed the rough eye phenotype, significantly lengthened AD Drosophila 's lifespan, and significantly enhanced the majority of the AD Drosophila 's mobility in a sex-dependent manner. The findings of this study suggest that p CA may have therapeutic benefits for AD. • p -Coumaric acid reduced fibrillation of Aβ42 in vitro. • PC12 neuronal cells were protected by p -Coumaric acid from cell death brought on by exposure to Aβ42. • The REP of AD Drosophila was partially recovered by feeding 500 μM p -Coumaric acid. • Administration of 500 μM p -Coumaric acid increased the longevity of AD Drosophila in a sex dependent manner. • Intake of 500 μM p -Coumaric acid improved the locomotive abilities AD Drosophila in a sex-dependent manner. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a long latency in the "prodromal" stage, for which there are currently no effective treatments. It is generally accepted that accurate diagnosis and subsequent treatment in the early stages of AD may lead to better therapeutic outcomes. Detection of body fluid biomarkers is an effective strategy for early AD diagnosis. Among them, amyloid β(1–42) (Aβ42), as one of the most important biomarkers of AD, plays a key role in the progression of AD. Currently, electrochemical biosensors offer many advantages in monitoring Aβ42 because they are fast, portable, and capable of on-site analysis. This article provides an overview of the dynamics of Aβ42 levels in biological fluids as AD progresses, followed by a detailed description of the design and analytical performance of various electrochemical sensors. Finally, the challenges of electrochemical sensors for AD diagnosis are discussed, and prospects and trends are outlined. A review of electrochemical biosensor assays for Aβ42, an important biomarker of Alzheimer's disease. [Display omitted] • The dynamics of Aβ42 levels in biological fluids as AD progresses are overviewed. • Advances in the design and analytical performance of various electrochemical Aβ42 biosensors are reviewed. • The possibility of applying the sensor in the practical analysis is presented. • The challenges, prospects and trends of electrochemical biosensors for Aβ42 detection are discussed. [ABSTRACT FROM AUTHOR]

ADAM 17, a disintegrin and metalloproteinase 17 belonging to the adamalysin protein family, is a Zn 2+ -dependent type-I transmembrane α-secretase protein. As a major sheddase, ADAM 17 acts as an indispensable regulator of chief cellular events and controls diverse cytokines, adhesion molecules, and growth factors. The signal peptide (residues 1-17) of ADAM 17 targets the protein to the secretory pathway and gets cleaved off afterward. No other function is documented for the ADAM 17 signal peptide (ADAM 17-SP) inside the cells. Here, we have taken a reductionist approach to understand the biophysical properties of ADAM 17-SP. Aiming to understand the possibility of aggregation, we found several aggregation-prone segments in the signal peptide. We performed in vitro experiments to show that the signal peptide forms amyloid-like aggregates in buffered conditions. We also studied its aggregation in the presence of sodium tripolyphosphate and heparin to correlate with the cellular conditions, as these biomolecules are naturally present inside cells. Further, we performed seeding experiments to observe the possibility of ADAM 17-SP aggregate interaction with the Aβ42 peptide. The results suggest that its seeds escalate the aggregation kinetics of the Aβ42 peptide and form heteromeric aggregates with it. We believe this finding could further intensify the aggregation studies on other signal peptides and shed light on the potential role of these segments other than signaling.

An amyloid precursor protein inhibitor (APPI) and amyloid beta 42 (Aβ42) are both subdomains of the human transmembrane amyloid precursor protein (APP). In the brains of patients with Alzheimer's disease (AD), Aβ42 oligomerizes into aggregates of various sizes, with intermediate, low-molecular-weight Aβ42 oligomers currently being held to be the species responsible for the most neurotoxic effects associated with the disease. Strategies to ameliorate the toxicity of these intermediate Aβ42 oligomeric species include the use of short, Aβ42-interacting peptides that either inhibit the formation of the Aβ42 oligomeric species or promote their conversion to high-molecular-weight aggregates. We therefore designed such an Aβ42-interacting peptide that is based on the β-hairpin amino acid sequence of the APPI, which exhibits high similarity to the β-sheet-like aggregation site of Aβ42. Upon tight binding of this 20-mer cyclic peptide to Aβ42 (in a 1:1 molar ratio), the formation of Aβ42 aggregates was enhanced, and consequently, Aβ42-mediated cell toxicity was ameliorated. We showed that in the presence of the cyclic peptide, interactions of Aβ42 with both plasma and mitochondrial membranes and with phospholipid vesicles that mimic these membranes were inhibited. Specifically, the cyclic peptide inhibited Aβ42-mediated mitochondrial membrane depolarization and reduced Aβ42-mediated apoptosis and cell death. We suggest that the cyclic peptide modulates Aβ42 aggregation by enhancing the formation of large aggregates─as opposed to low-molecular-weight intermediates─and as such has the potential for further development as an AD therapeutic.

The recent approval of antibody-based therapy for targeting the clearance of amyloid plaques fuels the research in designing small molecules and peptide inhibitors to target the aggregation of Aβ-peptides. Here, we report that the 15-residue ααγ-hybrid peptide not only inhibits the aggregation of soluble Aβ 42 into fibrils but also disintegrates the aggregated Aβ 42 fibrils into smaller assemblies. Further, the hybrid peptide completely rescues neuronal cells from the toxicity of Aβ 42 at equimolar concentrations. The shorter 10- and 12-mer peptides showed weak aggregation inhibition activity, while the fully hydrophobic 15-mer ααγ-hybrid peptide analogue showed no aggregation inhibition activity. Further, the 15-mer ααγ-hybrid peptide showed resistance against trypsin digestion and also nontoxic to the neuronal cells. The CD revealed that the peptide upon interaction induces a helix-type conformation in the Aβ 42 . This is in sharp contrast to the β-sheet conformation of Aβ 42 upon incubation. The two-dimensional-NMR (2D-NMR) analysis revealed a large perturbation in the chemical shifts of residues at the N-terminus. The presence of 15-mer peptide at an equimolar concentration of Aβ 42 showed less tendency for aggregation and also exhibited nontoxicity to the neuronal cells. The results reported here may be useful in designing new therapeutics for Alzheimer's disease.

Introduction: Alzheimer's disease  (AD) is characterized by decreased cerebrospinal fluid (CSF) Aβ42 and Aβ42/Aβ40 ratio. Aβ peptides can now be measured also in plasma and are promising peripheral biomarkers for AD. We evaluated the relationships of plasma Aβ species with their CSF counterparts, kidney function, and serum/CSF albumin ratio (Q-Alb) in AD patients., Materials and Methods: We measured plasma Aβ42 and Aβ40, as well as CSF AD biomarkers, with the fully automated Lumipulse platform in a cohort of N = 30 patients with clinical and neurochemical diagnosis of AD., Results: The two plasma Aβ peptides correlated strongly with each other (r = 0.7449), as did the corresponding CSF biomarkers (r = 0.7670). On the contrary, the positive correlations of plasma Aβ42, Aβ40, and Aβ42/Aβ40 ratio with their CSF counterparts and the negative correlation of plasma Aβ42/Aβ40 ratio with CSF P-tau181 were not statistically significant. Plasma levels of both Aβ species negatively correlated with estimated glomerular filtration rate (eGFR) (Aβ42: r = -0.4138; Aβ40: r = -0.6015), but plasma Aβ42/Aβ40 ratio did not. Q-Alb did not correlate with any plasma Aβ parameter., Discussion: Plasma Aβ42 and Aβ40 are critically influenced by kidney function; however, their ratio is advantageously spared from this effect. The lack of significant correlations between plasma Aβ species and their CSF counterparts is probably mainly due to small sample size and inclusion of only Aβ + individuals. Q-Alb is not a major determinant of plasma Aβ concentrations, highlighting the uncertainties about mechanisms of Aβ transfer between CNS and periphery., (© 2023. Fondazione Società Italiana di Neurologia.)

Aggregation of amyloid-β (Aβ) protein plays a central role in Alzheimer's disease. Because protein aggregation is a concentration-dependent process, rigorous investigations require accurate concentration measurements. Owing to the high aggregation propensity of Aβ protein, working solutions of Aβ are typically in the low micromolar range. Therefore, an ideal Aβ quantification method requires high sensitivity without sacrificing speed and accuracy. Absorbance at 280 nm is frequently used to measure Aβ concentration, but the sensitivity is low with only one tyrosine and no tryptophan residues in the Aβ sequence. Here we present a fluorescence method for Aβ quantification using fluorescamine, which gives high fluorescence upon reaction with primary amines. We show that, using hen egg white lysozyme as a standard, fluorescence correlates linearly with primary amine concentration across a wide range of fluorescamine concentrations, from 62.5 to 1000 µM. The maximal sensitivity of detection is achieved at a fluorescamine concentration of 250 µM or higher. The fluorescamine method is compatible with the presence of dimethyl sulfoxide, which is commonly used in the preparation of Aβ oligomers, and limits the use of absorbance at 280 nm due to its high background reading. Using aggregation kinetics, we show that the fluorescamine method gives accurate concentration measurements at low micromolar range and leads to highly consistent aggregation data. We recommend the fluorescamine assay to be used for routine and on-the-fly concentration determination in Aβ oligomerization and fibrillization experiments.

Background/Aims: Oligomerization of amyloid beta (Aβ) is a hypothesized step in the formation of plaques in Alzheimer’s disease (AD) but has been difficult to demonstrate in vivo in humans. As persons destined to develop familial AD (FAD) due to fully penetrant autosomal dominant mutations are essentially certain to develop the disease, they provide the opportunity to identify oligomers during the presymptomatic stage of the disease. Methods: We measured levels of Aβ42 using a conventional immunoassay and prefibrillar, fibrillar, and annular protofibrillar oligomers using polyclonal conformation-dependent antibodies in the cerebrospinal fluid (CSF) of 7 persons at risk for inheriting FAD mutations. Levels of oligomers were compared between FAD mutation carriers and noncarriers. Results: Compared to 2 noncarriers, annular protofibrillar oligomers were elevated, prefibrillar and fibrillar oligomers trended towards elevation and Aβ42 monomer trended towards being decreased in 5 FAD mutation carriers. Conclusion: Our data provide evidence for an identifiable elevation of CSF oligomers during the presymptomatic phase of FAD.

Analysis of the brain specific biomarkers amyloid β42 (Aβ42) and total tau (t-tau) protein in cerebrospinal fluid (CSF) has a sensitivity and specificity of more than 85% for differentiating Alzheimer’s Disease (AD) from non-demented controls. International guidelines are contradictory in their advice on the use of CSF biomarkers in AD diagnostics, resulting in a lack of consistency in clinical practice. We present three case reports that illustrate clinical practice according to the Dutch and European guidelines and portray the value of CSF biomarker analysis as an add-on diagnostic to the standard diagnostic workup for AD.

Alzheimer's disease (AD) is one of the world's most pressing health crises. AD is an incurable disease affecting more than 6.5 million Americans, predominantly the elderly, and in its later stages, leads to memory loss, dementia, and death. Amyloid β (Aβ) protein aggregates have been one of the pathological hallmarks of AD since its initial characterization. The early stages of Aβ accumulation and aggregation involve the formation of oligomers, which are considered neurotoxic and play a key role in further aggregation into fibrils that eventually appear in the brain as amyloid plaques. We have recently shown by combining ion mobility mass spectrometry (IM-MS) and atomic force microscopy (AFM) that Aβ42 rapidly forms dodecamers (12-mers) as the terminal oligomeric state, and these dodecamers seed the early formation of Aβ42 protofibrils. The link between soluble oligomers and fibril formation is one of the essential aspects for understanding the root cause of the disease state and is critical to developing therapeutic interventions. Utilizing a joint pharmacophore space (JPS) method, potential drugs have been designed specifically for amyloid-related diseases. These small molecules were generated based on crucial chemical features necessary for target selectivity. In this paper, we utilize our combined IM-MS and AFM methods to investigate the impact of three second-generation JPS small-molecule inhibitors, AC0201, AC0202, and AC0203, on dodecamer as well as fibril formation in Aβ42. Our results indicate that AC0201 works well as an inhibitor and remodeler of both dodecamers and fibril formation, AC0203 behaves less efficiently, and AC0202 is ineffective.

Alzheimer's disease (AD) is the most common neurological ailment worldwide. Its process comprises the unique aggregation of extracellular senile plaques composed of amyloid-beta (Aβ) in the brain. Aβ42 is the most neurotoxic and aggressive of the Aβ42 isomers released in the brain. Despite much research on AD, the complete pathophysiology of this disease remains unknown. Technical and ethical constraints place limits on experiments utilizing human subjects. Thus, animal models were used to replicate human diseases. The Drosophila melanogaster is an excellent model for studying both physiological and behavioural aspects of human neurodegenerative illnesses. Here, the negative effects of Aβ42-expression on a Drosophila AD model were investigated through three behavioural assays followed by RNA-seq. The RNA-seq data was verified using qPCR. AD Drosophila expressing human Aβ42 exhibited degenerated eye structures, shortened lifespan, and declined mobility function compared to the wild-type Control. RNA-seq revealed 1496 genes that were differentially expressed from the Aβ42-expressing samples against the control. Among the pathways that were identified from the differentially expressed genes include carbon metabolism, oxidative phosphorylation, antimicrobial peptides, and longevity-regulating pathways. While AD is a complicated neurological condition whose aetiology is influenced by a number of factors, it is hoped that the current data will be sufficient to give a general picture of how Aβ42 influences the disease pathology. The discovery of molecular connections from the current Drosophila AD model offers fresh perspectives on the usage of this Drosophila which could aid in the discovery of new anti-AD medications., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Alzheimer's disease (AD) is a common degenerative disease of the nervous system with serious impact on quality of life of patients and their families. With an aging population, AD has become a major public health problem in China and worldwide. However, the physiological and pathological mechanisms of AD have not been fully elucidated, and there is a lack of effective prevention and clinical treatment methods. Many studies have found that traditional Chinese medicine (TCM) has a good therapeutic effect on cognitive function in AD patients. Bu Shen Kai Qiao Fang (BSKQF) is one such Chinese herbal preparation used in the treatment of AD. We designed a protocol for a real-world clinical study of BSKQF combined with Donepezil hydrochloride (DH) to evaluate the efficacy and safety of this approach in the treatment of AD patients., Methods: This is a protocol for a real-world, multicenter, prospective, observational cohort study. The study will recruit 860 AD patients from four hospitals across China. Equal numbers of patients will be treated with BSKQF and DH or with DH only. The criteria for grouping are based primarily on patient preference. Outcome measures include scores on the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment Scale (MOCA) and will be recorded at baseline, and at one, two and three months after enrollment. The plasma Aβ42 and plasma Tau levels of participating patients will also be measured by ELISA at baseline and after 3 months of treatment. Safety metrics and adverse events (AEs) of participating patients will be monitored and recorded., Discussion: This study will evaluate the clinical efficacy and safety of BSKQF in the treatment of AD. The results will provide reliable evidence for the clinical application of BSKQF in the treatment of AD., Study Registration: Trial registration: Chinese Clinical Trial Registry, NO. ChiCTR2000039670, Registered 5 November 2020 https://www.chictr.org.cn/showprojEN.html?proj=63800., Competing Interests: The authors declare that they have no conflicts of interest in this work., (© 2023 Xu et al.)

The combination of decreased amyloid β42 (Aβ42) and increased total tau proteins (T-Tau) and phosphorylated tau (P-Tau) in cerebrospinal fluid (CSF) has recently been considered as a biological diagnostic criterion of Alzheimer’s disease (AD). Previous studies showed significant heterogeneity in CSF Aβ42 levels to discriminate AD from non-AD patients. It was also suggested that the CSF amyloid peptide β42/β40 ratio has better diagnostic performance than Aβ42 alone. The objective of the present study was to investigate the potential added value of determining CSF amyloid β40 peptide (Aβ40) for biological diagnosis of AD when CSF Aβ42 levels failed.CSF AD biomarkers were run in 2,171 samples from 1,499 AD and 672 non-AD patients. The following pathologic thresholds were used to define an AD-positive CSF biomarker profile: T-Tau ≥ 400 ng/L, P-Tau181 ≥ 60 ng/L and Aβ42 ≤ 700 ng/L. CSF Aβ40 was assayed in AD patients with CSF Aβ42 levels above 700 ng/L and non-AD patients with CSF Aβ42 levels below 700 ng/L. CSF Aβ40 levels were higher in AD than non-AD patients. The ROC curves of CSF Aβ40 and the Aβ42/Aβ40 ratio defined AD cut off values at 12,644 ng/L and 0.06 respectively. In AD patients with non-pathological CSF Aβ42, CSF Aβ40 concentration was able to correct 76.2% of cases when expressed as CSF Aβ42/Aβ40 ratio and 94.7% of cases when used alone. Using CSF Aβ42 and then CSF Aβ40, the percentage of misinterpreted AD patients fell to 1.0%.CSF Aβ40 concentration improved interpretation of Aβ42 level for the diagnosis of Alzheimer’s disease. CSF Aβ40 alone showed better diagnostic performance than the amyloid peptide Aβ42/Aβ40 ratio. The added value of determining CSF Aβ40 in AD diagnosis now needs confirming in a cohort of definite AD patients and to be completed with novel amyloid cascade biomarkers.

The goals of this work were i) to identify the interactions of amyloid-β (Aβ)42 under monomeric, oligomeric, and fibrillar forms with the extracellular matrix (ECM) and receptors, ii) to determine the influence of Aβ42 supramolecular organization on these interactions, and iii) to identify the molecular functions, biological processes, and pathways targeted by Aβ42 in the ECM. The ECM and cell surface partners of Aβ42 and its supramolecular forms were identified with protein and glycosaminoglycan (GAG) arrays (81 molecules in triplicate) probed by surface plasmon resonance imaging. The number of partners of Aβ42 increased upon its multimerization, ranging from 4 for the peptide up to 53 for the fibrillar aggregates. The peptide interacted only with ECM proteins but their percentage among Aβ42 partners decreased upon multimerization. Aβ42 and its supramolecular forms recognized different molecular features on their partners, and the partners of Aβ42 fibrillar forms were enriched in laminin IV-A, N-terminal, and EGF-like domains. Aβ42 oligomerization triggered interactions with receptors, whereas Aβ42 fibrillogenesis promoted binding to GAGs, proteoglycans, enzymes, and growth factors and the ability to interact with perineuronal nets. Fibril aggregation bind to further membrane proteins including tumor endothelial marker-8, syndecan-4, and discoidin-domain receptor-2. The partners of the Aβ42 supramolecular forms are enriched in proteins contributing to cell growth and/or maintenance, involved in integrin cell surface interactions and expressed in kidney cancer, preadipocytes, and dentin. In conclusion, the supramolecular assembly of Aβ42 governs its ability to interact in vitro with ECM proteins, remodeling and crosslinking ECM enzymes, proteoglycans, and receptors. [ABSTRACT FROM AUTHOR]

People with Down syndrome (DS) are at high risk of developing pathology similar to Alzheimer's disease (AD). Modeling of this pathology in vitro may be useful for studying this phenomenon. In this study, we analyzed three different cultures of neural cells carrying trisomy of chromosome 21, which were generated by directed differentiation from induced pluripotent stem cells (iPS cells). We report here that in vitro generated DS neural cells have abnormal metabolism of amyloid-β (Aβ) manifested by increased secretion and accumulation of Aβ granules of Aβ42 pathological isoform with upregulated expression of the APP gene. Additionally, we found increased expression levels of genes that are considered to be associated with AD (BACE2, RCAN1, ETS2, TMED10), as compared to healthy controls. Thus, the neural cells generated from induced pluripotent stem cells with DS reproduce initial cellular signs of AD-type pathology and can be useful tools for modeling and studying this variant of AD in vitro. [ABSTRACT FROM AUTHOR]

Background: Primary progressive aphasia (PPA) may present with three main clinical variants, namely nonfluent agrammatic (nfaPPA), semantic (sPPA), and logopenic (lPPA) subtypes. Frontotemporal lobar degenerations (FTLD) or Alzheimer's disease (AD) are the most common etiologies.Objective: To study the potential of cerebrospinal fluid (CSF) biomarkers for identifying the underlying pathology in patients with PPA.Methods: CSF levels of total tau protein (τT), amyloid-β peptide (Aβ42), and tau phosphorylated at threonine-181 (τP - 181) were measured by double sandwich, enzyme-linked immunosorbent assay (ELISA) in 43 patients with PPA, 26 patients with AD, and 17 healthy controls.Results: All patients could be classified as compatible with the AD or non-AD biomarker profile, either with the three biomarkers (90.7%) or their ratios, especially the τP - 181/Aβ42 ratio (9.3%). An AD-compatible biomarker profile was present in 39.5% of all PPA patients, specifically 22.2%, 35.7%, and 75% of nfaPPA, sPPA, and lPPA, respectively. In PPA patients with a non-AD profile (presumably FTLD), two different clusters could be identified according to the τP - 181/τT ratio, possibly corresponding to the two major FTLD pathologies (tau and TDP-43).Conclusion: CSF biomarkers may be a valuable tool for the discrimination between PPA patients with AD and non-AD pathophysiology and possibly between FTLD patients with tau and TDP-43 pathology. [ABSTRACT FROM AUTHOR]

Alzheimer disease is the most prevalent neurodegenerative disease and is associated with aggregation of Amyloid-β42 peptides. In mammals, Amyloid-β42 causes impaired neural stem/progenitor cell (NSPC) proliferation and neurogenesis, which exacerbate with aging. The molecular programs necessary to enhance NSPC proliferation and neurogenesis in our brains to mount successful regeneration are largely unknown. Therefore, to identify the molecular basis of effective brain regeneration, we previously established an Amyloid-β42 model in adult zebrafish that displayed Alzheimer-like phenotypes reminiscent of humans. Interestingly, zebrafish exhibited enhanced NSPC proliferation and neurogenesis after microinjection of Amyloid-β42 peptide. Here, we compare old and young fish to address the effects of aging on regenerative ability after Amyloid-β42 deposition. We found that aging does not affect the rate of NSPC proliferation but reduces the neurogenic response and microglia/macrophage activation after microinjection of Amyloid-β42 in zebrafish, suggesting an important link between aging, neuroinflammation, regenerative neurogenesis and neural stem cell plasticity. [ABSTRACT FROM AUTHOR]

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Alzheimer’s disease (AD) is the only one among top ten diseases in USA that cannot be cured, prevented or slowed down. At molecular level the mechanism of onset has been closely associated with mis-folding of Aβ40 and Aβ42 and is well supported by the genetic data for AD. Extensive research efforts have led to identification of factors and metal ions that could manipulate Aβ equilibrium, especially Ca 2+ . Previously, we reported selectively acceleration of Aβ42 fibril formation by Ca 2+ in vitro within physiological concentrations (BBA (2009) 1794:1536) . Aβ40 on the other hand did not appear to be significantly affected by Ca 2+ addition. In an effort to understand the distinctive behavior of Aβ40, we monitored changes of Aβ40 aggregation by intrinsic tyrosine fluorescence and CD and took different approaches for data processing. Our analysis of CD data indicates a complex effect induced by the addition of 2 mM Ca 2+ resulting in an increase in the rate of transformation from monomer to β-sheet rich fibrilar or intermediate species formation in Aβ40. Surprisingly, the kinetics observed by intrinsic fluorescence studies in this article and ThT, SEC or EM studies in our previous report were not able to unravel the existence of this effect in Aβ40. [ABSTRACT FROM AUTHOR]

Recent epidemiological and clinical data suggest that elevated serum homocysteine levels may increase the risk of developing Alzheimer's disease (AD), but the underlying mechanisms are unknown. We tested the hypothesis that high serum homocysteine concentration may increase amyloid beta-peptide (Aβ) levels in the brain and could therefore accelerate AD neuropathology. For this purpose, we mated a hyperhomocysteinemic CBStm1Unc mouse carrying a heterozygous dominant mutation in cystathionine-beta-synthase (CBS*) with the APP*/PS1* mouse model of brain amyloidosis. The APP*/PS1*/CBS* mice showed significant elevations of serum homocysteine levels compared to the double transgenic APP*/PS1* model of amyloidosis. Results showed that female (but not male) APP*/PS1*/CBS* mice exhibited significant elevations of Aβ40 and Aβ42 levels in the brain. Correlations between homocysteine levels in serum and brain Aβ levels were statistically significant. No increases in beta secretase activity or evidence of neuronal cell loss in the hyperhomocysteinemic mice were found.The causes of neuronal dysfunction and degeneration in AD are not fully understood, but increased production of Aβ seems to be of major importance. By unveiling a link between homocysteine and Aβ levels, these findings advance our understanding on the mechanisms involved in hyperhomocysteinemia as a risk factor for AD.

Aims: Previous studies have suggested that insulin‐like growth factor‐I (IGF‐I) deficiency may lead to cognitive deficits in neurodegenerative diseases such as Alzheimer's disease. The present study aimed to investigate the possible relationship between cognitive function and concentration of IGF‐I or amyloid beta protein (Aβ) in serum in Alzheimer's patients. Methods: A total of 81 Japanese patients were enrolled in this study. Concentrations of IGF‐I, Aβ42, and Aβ40 in serum were measured. Two neuropsychological tests, Mini‐Mental State Examination and Hasegawa's Dementia Scale‐Revised (HDS‐R), were also performed. Linear correlations among the age, serum IGF‐I, serum Aβ42 or Aβ40, Aβ42/Aβ40 ratio, Mini‐Mental State Examination or HDS‐R total score, and the scores for six HDS‐R subscales were analyzed by regression analysis. Results: IGF‐I showed a significant negative correlation with age (β = −0.357, P = 0.002) and a positive correlation with Aβ42/Aβ40 ratio (β = 0.318, P = 0.007). Serum IGF‐I and both the Mini‐Mental State Examination and the HDS‐R total score also correlated (β = 0.505, β = 0.524, P < 0.01). Among the HDS‐R subscales, ‘Recall’ (ρ = 0.379, P < 0.01), ‘Verbal fluency’ (ρ = 0.360, P < 0.01), and ‘Attention and calculation’ (ρ = 0.389, P < 0.01) showed significant positive correlations with serum IGF‐I. Conclusion: The results, specifically that lower serum IGF‐I was associated with cognitive impairment, suggest that metabolism of IGF‐I may be involved in the pathogenesis of cognitive deficits in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: The earliest stage of preclinical Alzheimer's disease (AD) is defined by low levels of cerebrospinal fluid (CSF) amyloid-β (Aβ42). However, covariance in longitudinal dynamic change of Aβ42 and tau in incipient preclinical AD is poorly understood.Objective: To examine dynamic interrelationships between Aβ42 and tau in preclinical AD.Methods: We followed 47 cognitively intact participants (CI) with available CSF data over four years in ADNI. Based on longitudinal Aβ42 levels in CSF, CI were classified into three groups: 1) Aβ42 stable with normal levels of Aβ42 over time (n = 15); 2) Aβ42 declining with normal Aβ42 levels at baseline but showing decline over time (n = 14); and 3) Aβ42 levels consistently abnormal (n = 18).Results: In the Aβ42 declining group, suggestive of incipient preclinical AD, CSF phosphorylated tau (p-tau) showed a similar longitudinal pattern of increasing abnormality over time (p = 0.0001). Correlation between longitudinal slopes of Aβ42 and p-tau confirmed that both trajectories were anti-correlated (rho = -0.60; p = 0.02). Regression analysis showed that Aβ42 slope (decreasing Aβ42) predicted p-tau slope (increasing p-tau) (R2 = 0.47, p = 0.03). Atrophy in the hippocampus was predicted by the interaction of Aβ42 and p-tau slopes (p <  0.0001) only in this incipient preclinical AD group. In all groups combined, memory decline was predicted by p-tau.Conclusions: The evolution of Aβ42 and p-tau CSF biomarkers in CI subjects follows an anti-correlated trajectory, i.e., as Aβ42 declined, p-tau increased, and thus was suggestive of strong temporal coincidence. Rapid pathogenic cross-talk between Aβ42 and p-tau thus may be evident in very early stages of preclinical AD. [ABSTRACT FROM AUTHOR]

Background: Dementia with Lewy bodies (DLB) symptoms are close to those of Alzheimer's disease (AD), and the differential diagnosis is difficult especially early in the disease. Unfortunately, AD biomarkers in cerebrospinal fluid (CSF), and more particularly Aβ1 - 42, appear to be altered in dementia with Lewy bodies (DLB). However, the level of these biomarkers has never been studied in the prodromal stage of the disease.Objective: To compare these biomarkers between DLB and AD, with a particular focus on the prodromal stage.Methods: A total of 166 CSF samples were collected at the memory clinic of Strasbourg. They were obtained from prodromal DLB (pro-DLB), DLB dementia, prodromal AD (pro-AD), and AD dementia patients, and elderly controls. Phospho-Tau181, total-Tau, Aβ42, and Aβ40 were measured in the CSF.Results: At the prodromal stage, contrary to AD patients, DLB patients' biomarker levels in the CSF were not altered. At the demented stage of DLB, Aβ42 levels were reduced as well as Aβ40 levels. Thus, the Aβ42/Aβ40 ratio remained unchanged between the prodromal and demented stages, contrary to what was observed in AD. Tau and Phospho-Tau181 levels were unaltered in DLB patients.Conclusions: We have shown that at the prodromal stage the DLB patients had no pathological profile. Consequently, CSF AD biomarkers are extremely useful for differentiating AD from DLB patients particularly at this stage when the clinical diagnosis is difficult. Thus, these results open up new perspectives on the interpretation of AD biomarkers in DLB. [ABSTRACT FROM AUTHOR]

Accruing evidence suggests that prion-like behavior of fibrillar forms of α-synuclein, β-amyloid peptide and mutant huntingtin are responsible for the spread of the lesions that characterize Parkinson disease, Alzheimer disease and Huntington disease, respectively. It is unknown whether these distinct protein assemblies are transported within and between neurons by similar or distinct mechanisms. It is also unclear if neuronal death or injury is required for neuron-to-neuron transfer. To address these questions, we used mouse primary cortical neurons grown in microfluidic devices to measure the amounts of α-synuclein, Aβ42 and HTTExon1 fibrils transported by axons in both directions (anterograde and retrograde), as well as to examine the mechanism of their release from axons after anterograde transport. We observed that the three fibrils were transported in both anterograde and retrograde directions but with strikingly different efficiencies. The amount of Aβ42 fibrils transported was ten times higher than that of the other two fibrils. HTTExon1 was efficiently transported in the retrograde direction but only marginally in the anterograde direction. Finally, using neurons from two distinct mutant mouse strains whose axons are highly resistant to neurodegeneration (Wld and Sarm1), we found that the three different fibrils were secreted by axons after anterograde transport, in the absence of axonal lysis, indicating that trans-neuronal spread can occur in intact healthy neurons. In summary, fibrils of α-synuclein, Aβ42 and HTTExon1 are all transported in axons but in directions and amounts that are specific of each fibril. After anterograde transport, the three fibrils were secreted in the medium in the absence of axon lysis. Continuous secretion could play an important role in the spread of pathology between neurons but may be amenable to pharmacological intervention. [ABSTRACT FROM AUTHOR]

A library of phage-displayed human single-chain Fv (scFv) antibodies was selected against the human amyloid-beta peptide (Aβ42). Two new anti-Aβ42 phage-displayed scFvs antibodies were obtained, and the sequences of their VH and Vκ genes were analyzed. A synthetic peptide based on the sequence of Ig heavy chain (VH) complementarity-determining region (HCDR3) of the clone with the highest recognition signal was generated and determined to bind to Aβ42 in ELISA. Furthermore, we showed for the first time that an HCDR3-based peptide had neuroprotective potential against Aβ42 neurotoxicity in rat cultured hippocampal neurons. Our results suggest that not only scFvs recognizing Aβ42 but also synthetic peptides based on the VH CDR3 sequences of these antibodies may be novel potential candidates for small molecule-based Alzheimer's disease (AD) therapy.

Human FPRL1 and its mouse homologue FPR2 are functional receptors for several exogenous and host-derived chemotactic peptides, including amyloid β42 (Aβ42), a critical pathogenic factor in Alzheimer's disease. We investigated the effect of TNFα on the expression and function of FPR2 in mouse microglial cells, a crucial inflammatory cell type in the CNS. Primary murine microglia and a cell line N9 in resting state expressed low levels of FPR2 gene and lacked the response to chemotactic agonists for this receptor. Incubation with TNFα, however, increased microglial expression of FPR2 gene, in association with potent chemotactic responses to FPR2-specific agonists including Aβ42. The effect of TNFα was dependent on the p55 TNFα receptor and activation of MAP kinase p38. TNFα concomitantly down-regulated microglial response to the chemokine SDF-1α. Thus, by selectively up-regulating FPR2 in microglia, TNFα has the capacity to amplify host response in inflammatory diseases in the CNS.

Alzheimer's disease (AD) is the most common neurodegenerative disorder in the world. The aggregation of both amyloid beta (Aβ) peptides extracellularly and Tau proteins intracellularly plays key roles in the pathological consequences of AD, which lead to cholinergic neurodegeneration and eventually death. Currently, there are no effective methods to stop the progression of AD. Using ex vivo, in vivo and clinical approaches, we investigated the functional effects of plasminogen on the widely used FAD, Aβ42 oligomer or Tau intracranial injection-induced AD mouse model and explored its therapeutic effects on patients with AD. The results show that intravenously injected plasminogen rapidly crosses the blood‒brain barrier (BBB); increases plasmin activity in the brain; colocalizes with and effectively promotes the clearance of Aβ42 peptide and Tau protein deposits ex vivo and in vivo; increases the choline acetyltransferase (ChAT) level and decreases the acetylcholinesterase (AChE) activity; and improves the memory functions. Clinically, when GMP-level plasminogen was administered to 6 AD patients for 1-2 weeks, their average scores on the Minimum Mental State Examination (MMSE), which is a standard scoring system used to measure the memory loss and cognitive deficits, were extremely significantly improved by 4.2 ± 2.23 points, e.g., an average increase from 15.5 ± 8.22 before treatment to 19.7 ± 7.09 after treatment. The preclinical study and pilot clinical study suggest that plasminogen is effective in treating AD and may be a promising drug candidate., Competing Interests: Declaration of competing interest J.L. founded Talengen Institute of Life Sciences. The institute has applied patents on the use of plasminogen and is developing natural and recombinant plasminogen as a drug candidate to treat Alzheimer's disease and other neurological diseases. Other authors have declared no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is a multifactorial disorder that affects cognitive functioning, behavior, and neuronal properties. The neuronal dysfunction is primarily responsible for cognitive decline in AD patients, with many causal factors including plaque accumulation of Aβ42. Neural hyperactivity induced by Aβ42 deposition causes abnormalities in neural networks, leading to alterations in synaptic activity and interneuron dysfunction. Even though neuroimaging techniques elucidated the underlying mechanism of neural connectivity, precise understanding at the cellular level is still elusive. Previous multielectrode array studies have examined the neuronal network modulation in in vitro cultures revealing the relevance of ion channels and the chemical modulators in the presence of Aβ42. In this study, we investigated neuronal connectivity and dynamic changes using a high-density multielectrode array, particularly looking at network-wide parameter changes over time. By comparing the neuronal network between normal and Aβ42treated neuronal cultures, it was possible to discover the direct pathological effect of the Aβ42 oligomer altering the network characteristics. The detrimental effects of the Aβ42 oligomer included not only a decline in spike activation but also a qualitative impairment in neural connectivity as well as a disorientation of dispersibility. As a result, this will improve our understanding of how neural networks are modified during AD progression.

Objective: To detect and analyze the serum levels of Aβ42, ApoJ, NO and IL-6 in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Methods: The serum samples of MCI, AD patients and normal elderly controls (NC) were collected, the levels of Aβ42, ApoJ, NO and IL-6 were measured by ELISA. Results: (1)The serum level of Aβ42 was significantly higher in the patients with MCI than that of NC (P<0.05), the serum level of Aβ42 had no significant difference between AD and NC. (2)The level of ApoJ in MCI and AD group were all increased in comparison with that of NC, the level of ApoJ in AD was significantly increased in comparison with that of MCI (P<0.05). (3)Compared with NC group, MCI and AD had notably higher levels of NO (P<0.05), but the level of NO had no significant difference between MCI and AD. (4)The levels of IL-6 of MCI and AD were significantly higher than that of NC. The IL-6 level of AD was higher than that of MC (P<0.05). (5) The level of IL-6 in AD group had a negative correlation with MMSE score (r=-0.37, P<0.05). Conclusions: Serum Aβ42, ApoJ levels may be used in the diagnosis of MCI, and the levels of ApoJ, NO and IL-6 may help to predict the diagnosis of AD and evaluate the situation of disease. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the leading cause of dementia and the most common neurodegenerative disorder. AD is mostly a sporadic disorder and its main risk factor is age, but mutations in three genes that promote the accumulation of the amyloid-β (Aβ42) peptide revealed the critical role of amyloid precursor protein (APP) processing in AD. Neurofibrillary tangles enriched in tau are the other pathological hallmark of AD, but the lack of causative tau mutations still puzzles researchers. Here, we describe the contribution of a powerful invertebrate model, the fruit fly Drosophila melanogaster , to uncover the function and pathogenesis of human APP, Aβ42, and tau. APP and tau participate in many complex cellular processes, although their main function is microtubule stabilization and the to-and-fro transport of axonal vesicles. Additionally, expression of secreted Aβ42 induces prominent neuronal death in Drosophila , a critical feature of AD, making this model a popular choice for identifying intrinsic and extrinsic factors mediating Aβ42 neurotoxicity. Overall, Drosophila has made significant contributions to better understand the complex pathology of AD, although additional insight can be expected from combining multiple transgenes, performing genome-wide loss-of-function screens, and testing anti-tau therapies alone or in combination with Aβ42. [ABSTRACT FROM AUTHOR]

Background Alterations in the CSF/serum albumin ratio (Qalb) is currently recognized as one of the most reliable markers of blood–brain barrier impairment and blood-CSF barrier permeability, but its potential role as a biomarker in the differential diagnosis of neurological diseases has been poorly analysed. Methods We evaluated Qalb and core CSF biomarkers (Tau, p-Tau and Aβ42) in a large patient population of neurological and neurodegenerative cases. Diagnostic test evaluation was assessed by ROC-AUC analysis. Results In the differential diagnostic analysis, increased Qalb was found in dementia with Lewy bodies (DLB) patients compared to other diseases, either individually or stratified in non-dementia and dementia groups. When clinical groups were analysed individually and compared to controls, Qalb was also increased in stroke and Parkinson's disease dementia (PDD) cases, but not in Parkinson's disease (PD). Qalb in DLB cases correlate with CSF Aβ42 levels but not with Tau and p-Tau levels. Due to the lower CSF Aβ42 levels in DLB compared to PD and PDD, the potential clinical applicability of Qalb with respect to the DLB diagnosis is increased in combination with CSF Aβ42 analysis. Conclusions The present study demonstrates increased Qalb in synucleinopathies associated with dementia revealing a potential new clinical approach for the differential diagnosis of DLB. [ABSTRACT FROM AUTHOR]

The combination of decreased amyloid β42 (Aβ42) and increased total tau proteins (T-Tau) and phosphorylated tau (P-Tau) in cerebrospinal fluid (CSF) has recently been considered as a biological diagnostic criterion of Alzheimer's disease (AD). Previous studies showed significant heterogeneity in CSF Aβ42 levels to discriminate AD from non-AD patients. It was also suggested that the CSF amyloid peptide β42/β40 ratio has better diagnostic performance than Aβ42 alone. The objective of the present study was to investigate the potential added value of determining CSF amyloid β40 peptide (Aβ40) for biological diagnosis of AD when CSF Aβ42 levels failed. CSF AD biomarkers were run in 2,171 samples from 1,499 AD and 672 non-AD patients. The following pathologic thresholds were used to define an AD-positive CSF biomarker profile: T-Tau = 400 ng/L, P-Tau181 ≥ 60 ng/L, and Aβ42 ≤ 700 ng/L. CSF Aβ40 was assayed in AD patients with CSF Aβ42 levels above 700 ng/L and non-AD patients with CSF Aβ42 levels below 700 ng/L. CSF Aβ40 levels were higher in AD than non-AD patients. The receiver operator characteristic curves of CSF Aβ40 and the Aβ42/Aβ40 ratio defined AD cut-off values at 12,644 ng/L and 0.06, respectively. In AD patients with non-pathological CSF Aβ42, CSF Aβ40 concentration was able to correct 76.2% of cases when expressed as CSF Aβ42/Aβ40 ratio and 94.7% of cases when used alone. Using CSF Aβ42 and then CSF Aβ40, the percentage of misinterpreted AD patients fell to 1.0%. CSF Aβ40 concentration improved interpretation of Aβ42 level for the diagnosis of AD. CSF Aβ40 alone showed better diagnostic performance than the amyloid peptide Aβ42/Aβ40 ratio. The added value of determining CSF Aβ40 in AD diagnosis now needs confirming in a cohort of definite AD patients and to be completed with novel amyloid cascade biomarkers. [ABSTRACT FROM AUTHOR]

Purpose:In addition to testing blood, cerebrospinal fluid (CSF) has been analyzed in the search for biomarkers. The aim of this study was to identify biomarkers in CSF for neuropsychological symptoms in early-stage late-onset Alzheimer's disease (LOAD).Methods:CSF levels of beta-amyloid 1-42 (Aβ42), F2-isoprostanes (F2-IsoPs) and F4-neuroprostanes (F4-NPs) were assayed in nine patients with mild Alzheimer's disease (AD), nine patients with amnestic mild cognitive impairment (a-MCI) and nine individuals with normal mental function. The three groups underwent neuropsychological testing.Results:CSF levels of F2-IsoPs and F4-NPs did not significantly differ among the three groups. Aβ42 in CSF was significantly higher in the control group compared with the mild AD group (p< 0.001) and a-MCI group (p= 0.03). There was a significant positive correlation between the level of F2-IsoPs and Aβ42 in the a-MCI group and between the level of F2-IsoPs and F4-NPs in the mild AD group. In comparisons between the mild AD group and a-MCI group combined, the cognitive impairment (CI) group, with the control group, the median levels of F2-IsoPs and F4-NPs were significantly higher in the CI group and median level of Aβ42 was significantly lower in the CI group. Both the levels of F2-IsoPs and Aβ42 were significantly negatively correlated with paranoid and delusional ideation and total score for the Behavioral Pathology in Alzheimer's Disease Scale (BEHAVE-AD).Conclusions:The findings suggest CSF levels of Aβ42 and F2-IsoPs are associated with the severity of neuropsychological symptoms. [ABSTRACT FROM PUBLISHER]

Aggregation of β-amyloid (A β) into oligomers and further into fibrils is hypothesized to be a key factor in pathology of Alzheimer's disease ( AD). In this study, mapping and docking were used to study the binding of ligands to protofibrils. It was followed by molecular simulations to understand the differences in interactions of known therapeutic agents such as curcumin, fluorescence-based amyloid staining agents such as thioflavin T, and diagnostic agents such as florbetapir ( AV45), with A β protofibrils. We show that therapeutic agents bind to and distort the protofibrils, thus causing destabilization or prevention of oligomerization, in contrast to diagnostic agents which bind to but do not distort such structures. This has implications in the rational design of ligands, both for diagnostics and therapeutics of AD. [ABSTRACT FROM AUTHOR]

We demonstrated previously that ginsenoside Rg3 enhances the expression of macrophage scavenger receptor class A (SRA) and amyloid β peptide 1–42 (Aβ42) uptake in BV2 cells. In this study, we investigated the biochemical and mechanistic roles of Rg3 in human microglia and animal models to identify the determinants that participate in restoring memory and learning in brains disrupted by the Aβ42 peptide. SRA was expressed highly in Rg3-treated rats, and learning and memory functions were maintained at a normal level after the infusion of Aβ42. SRA-transfected HMO6 human microglial cells (HMO6.hSRA) overexpressed SRA and took up a remarkable amount of Aβ42. Rg3-treated HMO6 cells showed highly enhanced SRA expression and dramatically promoted Aβ42 uptake. Moreover, high levels of clathrin and caveolin1 supported the roles of Rg3 in endocytic biogenesis by activating p38 and extracellular signal-regulated protein kinase signaling. Notably, both neprilysin (NEP) and insulin-degrading enzyme (IDE) were significantly expressed by Rg3, suggesting independent and compensatory hydrolytic activity for the Aβ peptide. In conclusion, Rg3 successfully triggered Aβ42 uptake via SRA and clathrin-/caveolae-mediated endocytic mechanisms and further contributed to accelerate the degradation of Aβ peptide via the increase of intracellular NEP and IDE, which may be a promising Alzheimer׳s disease therapy. [ABSTRACT FROM AUTHOR]

The abnormal accumulation of amyloid- β (A β) peptide in the brain is one of the most important hallmarks of Alzheimer's disease. A β is an aggregation-prone and toxic polypeptide with 39-43 residues, derived from the amyloid precursor protein proteolysis process. According to the amyloid hypothesis, abnormal accumulation of A β in the brain is the primary influence driving Alzheimer's disease pathologies. Among all kinds of A β isoforms, A β40 and A β42 are believed to be the most important ones. Although these two kinds of A β differ only in two amino acid residues, recent studies show that they differ significantly in their metabolism, physiological functions, toxicities, and aggregation mechanism. In this review, we mainly summarize the similarities and differences between A β42 and A β40, recent studies on selective inhibitors as well as probes will also be mentioned. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Amyloid-beta (Aβ) peptides, Aβ 1–42 (Aβ42) and Aβ43 in particular, cause neurotoxicity and cell death in the brain of Alzheimer's disease (AD) at higher concentrations. Carnosic acid (CA), a phenolic diterpene compound in the labiate herbs rosemary and sage, serves as an activator for neuroprotective and neurotrophic functions in brain cells. We investigated the effect of CA on apoptosis induced by Aβ42 or Aβ43 in cultured SH-SY5Y human neuroblastoma cells. Treatment of the cells with Aβ42 or Aβ43 (monomer, 10 μM each) induced apoptosis, which was confirmed by the cleavage of poly-(ADP-ribose) polymerase (PARP) and apoptosis-inducing factor (AIF). Concurrently, the Aβ treatment induced the activation of caspase (Casp) cascades including an effector Casp (Casp3) and initiator Casps (Casp4, Casp8 and Casp9). Pretreatment of the cells with CA (10 μM) partially attenuated the apoptosis induced by Aβ42 or Aβ43. CA pretreatment also reduced the cellular oligomers of Aβ42 and Aβ43. These results suggest that CA suppressed the activation of Casp cascades by reducing the intracellular oligomerization of exogenous Aβ42/43 monomer. The ingestion of an adequate amount of CA may have a potential in the prevention of Aβ-mediated diseases, particularly AD. [ABSTRACT FROM AUTHOR]