Protein Aβ Research Articles

A Novel Strategy for Alzheimer's Disease Based on the Regulatory Effect of Amyloid-β on Gut Flora.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases worldwide. The accumulation of amyloid-β (Aβ) protein and plaque formation in the brain are two major causes of AD. Interestingly, growing evidence demonstrates that the gut flora can alleviate AD by affecting amyloid production and metabolism. However, the underlying mechanism remains largely unknown. This review will discuss the possible association between the gut flora and Aβ in an attempt to provide novel therapeutic directions for AD treatment based on the regulatory effect of Aβ on the gut flora.

A proteomics analysis of 5xFAD mouse brain regions reveals the lysosome-associated protein Arl8b as a candidate biomarker for Alzheimer’s disease

BackgroundAlzheimer’s disease (AD) is characterized by the intra- and extracellular accumulation of amyloid-β (Aβ) peptides. How Aβ aggregates perturb the proteome in brains of patients and AD transgenic mouse models, remains largely unclear. State-of-the-art mass spectrometry (MS) methods can comprehensively detect proteomic alterations, providing relevant insights unobtainable with transcriptomics investigations. Analyses of the relationship between progressive Aβ aggregation and protein abundance changes in brains of 5xFAD transgenic mice have not been reported previously.MethodsWe quantified progressive Aβ aggregation in hippocampus and cortex of 5xFAD mice and controls with immunohistochemistry and membrane filter assays. Protein changes in different mouse tissues were analyzed by MS-based proteomics using label-free quantification; resulting MS data were processed using an established pipeline. Results were contrasted with existing proteomic data sets from postmortem AD patient brains. Finally, abundance changes in the candidate marker Arl8b were validated in cerebrospinal fluid (CSF) from AD patients and controls using ELISAs.ResultsExperiments revealed faster accumulation of Aβ42 peptides in hippocampus than in cortex of 5xFAD mice, with more protein abundance changes in hippocampus, indicating that Aβ42 aggregate deposition is associated with brain region-specific proteome perturbations. Generating time-resolved data sets, we defined Aβ aggregate-correlated and anticorrelated proteome changes, a fraction of which was conserved in postmortem AD patient brain tissue, suggesting that proteome changes in 5xFAD mice mimic disease-relevant changes in human AD. We detected a positive correlation between Aβ42 aggregate deposition in the hippocampus of 5xFAD mice and the abundance of the lysosome-associated small GTPase Arl8b, which accumulated together with axonal lysosomal membranes in close proximity of extracellular Aβ plaques in 5xFAD brains. Abnormal aggregation of Arl8b was observed in human AD brain tissue. Arl8b protein levels were significantly increased in CSF of AD patients.ConclusionsWe report a comprehensive biochemical and proteomic investigation of hippocampal and cortical brain tissue derived from 5xFAD transgenic mice, providing a valuable resource to the neuroscientific community. We identified Arl8b, with significant abundance changes in 5xFAD and AD patient brains. Arl8b might enable the measurement of progressive lysosome accumulation in AD patients and have clinical utility as a candidate biomarker.

Electrochemical Immunosensors Developed for Amyloid-Beta and Tau Proteins, Leading Biomarkers of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurological disease and a serious cause of dementia, which constitutes a threat to human health. The clinical evidence has found that extracellular amyloid-beta peptides (Aβ), phosphorylated tau (p-tau), and intracellular tau proteins, which are derived from the amyloid precursor protein (APP), are the leading biomarkers for accurate and early diagnosis of AD due to their central role in disease pathology, their correlation with disease progression, their diagnostic value, and their implications for therapeutic interventions. Their detection and monitoring contribute significantly to understanding AD and advancing clinical care. Available diagnostic techniques, including magnetic resonance imaging (MRI) and positron emission tomography (PET), are mainly used to validate AD diagnosis. However, these methods are expensive, yield results that are difficult to interpret, and have common side effects such as headaches, nausea, and vomiting. Therefore, researchers have focused on developing cost-effective, portable, and point-of-care alternative diagnostic devices to detect specific biomarkers in cerebrospinal fluid (CSF) and other biofluids. In this review, we summarized the recent progress in developing electrochemical immunosensors for detecting AD biomarkers (Aβ and p-tau protein) and their subtypes (AβO, Aβ(1-40), Aβ(1-42), t-tau, cleaved-tau (c-tau), p-tau181, p-tau231, p-tau381, and p-tau441). We also evaluated the key characteristics and electrochemical performance of developed immunosensing platforms, including signal interfaces, nanomaterials or other signal amplifiers, biofunctionalization methods, and even primary electrochemical sensing performances (i.e., sensitivity, linear detection range, the limit of detection (LOD), and clinical application).

Computationally Designed Small Molecules Disassemble Both Soluble Oligomers and Protofibrils of Amyloid β-Protein Responsible for Alzheimer's Disease.

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.

Ethyl acetate extract of Gastrodiaelata protects Caenorhabditis elegans from oxidative stress and amyloid β peptide toxicity.

Gastrodia elata Blume is a traditional Chinese medicine with a long history, which has numerous pharmacological activities, such as anti-inflammation, anti-oxidation and protection of nerves. The present study investigated the regulatory effect of ethyl acetate extract of Gastrodia elata (EEGE) on the β-amyloid (Aβ) toxicity of Caenorhabditis elegans (C. elegans). First, the main components of EEGE were analyzed using high-performance liquid chromatography, and the total phenols, total flavonoids and total antioxidant capacity of EEGE were determined. Next, the regulation effect of EEGE on Aβ-induced toxicity of C. elegans was evaluated through experiments on nematode paralysis, lifespan, oxidative and heat stress, locomotor ability, reproductive ability, reactive oxygen species (ROS) level, Aβ aggregation test, malondialdehyde (MDA) level, catalase (CAT) activity and superoxide dismutase (SOD) activity. Finally, the mechanism of EEGE was elucidated using RNA sequencing (RNA-Seq) and the expression levels of related genes were verified using quantitative PCR. The present study revealed that the main components of EEGE included phosphorylated (p)-hydroxybenzyl alcohol, p-hydroxybenzaldehyde and 4,4'-dihydroxydiphenylmethane, possessing strong in vitro free radical scavenging and reducing abilities. In addition, after the intervention of EEGE, the paralysis of nematodes could be delayed, the survival time of the nematodes was prolonged, the survival rate of the nematodes under stress (high temperature and oxidation) conditions was improved, the activity capacity and reproductive capacity of the nematodes were improved, the activities of SOD and CAT were improved and the levels of ROS and MDA were reduced. Notably, EEGE directly inhibited Aβ plaque aggregation in nematodes. RNA-Seq analysis showed that EEGE regulated metabolism and longevity-related genes, and these genes were regulated by the insulin/IGF-1 signaling (IIS) pathway. Therefore, the present study hypothesized that the regulatory mechanism of EEGE was significantly related to the IIS pathway. The present research results demonstrated that the protective effect of EEGE on transgenic C. elegans was to reduce Aβ protein aggregation, improve the in vivo antioxidant level, effectively remove free radicals and to regulate the expression of genes related to IIS pathway, thereby reducing Aβ-induced toxicity and delaying nematode paralysis.

A new ITO-based Aβ42 biosensor for early detection of Alzheimer's disease

In this study, a novel label-free impedimetric immunosensor was fabricated for rapid, selective, and sensitive quantitative analysis of Aβ42 protein for use in the diagnosis of Alzheimer's disease. The immunosensor was fabricated using inexpensive and disposable indium tin oxide polyethylene terephthalate (ITO-PET) electrodes. After the electrodes were modified with 3-glycidoxypropyldimethoxymethylsilane (GPDMMS), the antibody specific to the Aβ42 protein (anti-Aβ42) was immobilized. The affinity interaction between anti-Aβ42 and Aβ42 in the immobilization steps in immunosensor fabrication and in the quantitation of Aβ42 were analyzed using Electrochemical Impedance Spectroscopy (EIS) and Cyclic Voltammetry (CV) techniques. Additionally, the morphological changes occurring on the electrode surface during each immobilization step were imaged using scanning electron microscopy (SEM). The linear detection range of the immunosensor was determined as 1–100 pg/mL with the limit of detection value of 0.37 pg/mL. Analytical properties of the biosensor, including reproducibility, repeatability, storage stability, selectivity, and regeneration were investigated. The kinetic behavior of antibody-antigen complex formation was determined for the first time using single frequency impedance (SFI) analysis on an Aβ42 biosensor. The potential for use of the immunosensor in clinical studies was demonstrated by analysis of Aβ42 in commercially purchased human serum.

Endocytic pathways of pathogenic protein aggregates in neurodegenerative diseases.

Endocytosis is the fundamental uptake process through which cells internalize extracellular materials and species. Neurodegenerative diseases (NDs) are characterized by a progressive accumulation of intrinsically disordered protein species, leading to neuronal death. Misfolding in many proteins leads to various NDs such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and other disorders. Despite the significance of disordered protein species in neurodegeneration, their spread between cells and the cellular uptake of extracellular species is not entirely understood. This review discusses the major internalization mechanisms of the different conformer species of these proteins and their endocytic mechanisms. We briefly introduce the broad types of endocytic mechanisms found in cells and then summarize what is known about the endocytosis of monomeric, oligomeric and aggregated conformations of tau, Aβ, α-Syn, Huntingtin, Prions, SOD1, TDP-43 and other proteins associated with neurodegeneration. We also highlight the key players involved in internalizing these disordered proteins and the several techniques and approaches to identify their endocytic mechanisms. Finally, we discuss the obstacles involved in studying the endocytosis of these protein species and the need to develop better techniques to elucidate the uptake mechanisms of a particular disordered protein species.

Effect of Curcumin on Cognitive Behavior and Pathological Characteristics of the Hippocampus in Mice with Inherent Alzheimer's Disease.

This study examined the effect of curcumin on pathological manifestations and clearance of amyloid β peptide (Aβ) in the hippocampus of 8-month-old transgenic APP/PS1 mice with inherent Alzheimer's disease. APP/PS1 mice and the age-matched wild-type controls were subjected to 3 behavioral tests: open field, new object recognition, and Morris water maze. Expression of Aβ, APP, CTF, BACE1, IDE, NEP, and LRP1 proteins in the extracted hippocampal tissue was evaluated by Western blotting. The distribution and the quantity of amyloid plaques and the spread of microglia in the hippocampus were determined by immunofluorescence. The contents of Aβ40 and Aβ42 in the hippocampus were assayed and analyzed on Simoa HD-1 analyzer. The proteins interacting with Aβ in the hippocampus of APP/PS1 mice were detected by co-immunoprecipitation. Curcumin significantly reduced motor hyperactivity in the open-field test, improved short-term recognition memory, spatial learning, and reference memory in APP/PS1 mice. In the hippocampus of APP/PS1 mice, curcumin significantly diminished the elevated Aβ levels and inhibited microglia proliferation. At the same time, curcumin had no effect on Aβ production, extracellular enzymatic hydrolysis, and LRP1-mediated outward transport, but enhanced Aβ clearance by activation of the intracellular ubiquitin-proteasome system and related peripheral mechanisms. Thus, curcumin improves the learning and memory abilities of APP/PS1 mice and reduces the pathological accumulation of Aβ in the brain.

Changes in Aβ42, Neprilysin, and γ-Secretase in the Hippocampus of Male Rats Alzheimer’s model: The Effects of Aerobic Training and Omega-3 Intake

Background: Alzheimer›s disease (AD) is characterized by excessive deposition of the amyloid-β peptide (Aβ) in the central nervous system and reducing its level is the goal of many medications. This study aimed to investigate the effect of aerobic training and omega-3 intake on Aβ42, neprilysin, and γ-secretase levels in the hippocampus of male rats Alzheimer›s model. Methods: Fifty male Wistar rats (age: 12 weeks-old and weight: 222.31±11.91 g), were divided into the five groups including control Alzheimer’s (AC), Alzheimer’s with omega-3 intake (AO), Alzheimer’s training (AT), Alzheimer’s with omega-3 intake and training (AOT) and Healthy Control (HC). AD was induced by the injection of homocysteine (60mM) into the rat brain ventricle. Training on the treadmill with a speed of 20 m/min (60 minutes and 5 days/week) was applied. The supplement group received omega-3 supplement 800 mg/kg of body weight, daily for eight weeks. Levels of Aβ42, γ-secretase, and neprilysin protein were measured using ELISA method. In data analysis, one-way ANOVA and Tukey test as post hoc were used (P<0.05). Results: The obtained results showed that the level of Aβ42 in the hippocampus of AC group was significantly higher than that of the HC group (P=0.001). Also, the level of Aβ42 in the hippocampus of AC group was significantly higher as compared to AO, AT, and AOT groups (P values 0.001, 0.007, and 0.003 respectively). The γ-Secretase level in the hippocampus of AC group was significantly higher than that in the HC group (P=0.001). Moreover, the γ-secretase levels in the hippocampus of the AC group were significantly higher compared to AO, AT, and AOT groups (P values: 0.002, 0.001, and 0.001 respectively). There was no significant difference in neprilysin levels of the hippocampus among the research groups (P=0.534). Conclusion: It appears that exercise training and omega-3 consumption, can affect amyloidogenic pathways through reducing the level of γ-secretase, and lead to reduced level of hippocampus Aβ in AD subjects. Therefore, aerobic exercise training and omega-3 intake can be studied as a complementary therapy in Alzheimer’s patients.

Alcohol consumption may be associated with postoperative delirium in the elderly: the PNDABLE study

ObjectivesThis study aimed to reveal the relationship between alcohol consumption and Postoperative delirium (POD) in the elderly.MethodsWe selected 252 patients from the Perioperative Neurocognitive Disorder And Biomarker Lifestyle (PNDABLE ) study. Patients in the PNDABLE database have been measured for Alzheimer-related biomarkers in CSF (Aβ40, Aβ42, P-tau, and tau protein). Mini-Mental State Examination (MMSE) was used to assess the preoperative mental status of patients. POD was diagnosed using the Confusion Assessment Method (CAM) and assessed for severity using the Memorial Delirium Assessment Scale (MDAS). Logistic regression analysis was utilized to explore the association of alcohol consumption with POD. Linear regression analysis was used to study the relationship between alcohol consumption and CSF biomarkers. Mediation analyses with 10,000 bootstrapped iterations were used to explore the mediation effects. Finally, we constructed the receiver operating characteristic (ROC) curve and the nomogram model to evaluate the efficacy of alcohol consumption and CSF biomarkers in predicting POD. ResultThe incidence of POD was 17.5%. Logistic regression showed that alcohol consumption (OR = 1.016, 95%CI 1.009–1.024, P < 0.001) is a risk factor for POD. What’s more, Aβ42 is a protective factor for POD (OR = 0.993, 95%CI 0.989–0.997, P < 0.05), and P-Tau was a risk factor for POD (OR = 1.093, 95%CI 1.022–1.168, P < 0.05). Linear regression analysis revealed that alcohol consumption was negatively associated with CSF Aβ42 (β = -0.638, P < 0.001) in POD patients. Mediation analyses showed that alcohol consumption is likely to partially mediate POD through Aβ42 (proportion:14.21%). ROC curve showed that alcohol consumption (AUC = 0.904; P < 0.001) exhibited a relatively better discriminatory ability in POD prediction compared to Aβ42 (AUC = 0.798; P < 0.001). The calibration curve indicated a good nomogram prediction (P = 0.797).ConclusionAlcohol consumption is a risk factor for POD (particularly for those with > 24 g a day on average) in the elderly, and contributes to POD through the mediation of Aβ42.

Recent Trends in Active and Passive Immunotherapies of Alzheimer's Disease.

In the elderly, a debilitating condition known as dementia, which is a major health concern, is caused by Alzheimer's disease (AD). Despite promising advances by researchers, there is currently no way to completely cure this devastating disease. It is illustrated by the deposition of amyloid β-peptide (Aβ) plaques that are followed by neural dysfunction and cognitive decline. Responses against AD activate an immune system that contributes to and accelerates AD pathogenesis. Potential efforts in the field of pathogenesis have prompted researchers to explore novel therapies such as active and passive vaccines against Aβ proteins (Aβ immunotherapy), intravenous immunoglobulin, and tau immunotherapy, as well as targets that include microglia and several cytokines for the treatment of AD. Aims are now underway by experts to begin immunotherapies before the clinical manifestation, which is made possible by improving the sensitivity of biomarkers used for the diagnosis of AD to have better outcome measures. This review provides an overview of approved immunotherapeutic strategies for AD and those currently being investigated in clinical trials. We examine their mechanisms of action and discuss the potential perspectives and challenges associated with immunotherapies for AD.

The Mechanisms of the Roles of α-Synuclein, Amyloid-β, and Tau Protein in the Lewy Body Diseases: Pathogenesis, Early Detection, and Therapeutics.

Lewy body diseases (LBD) are pathologically defined as the accumulation of Lewy bodies composed of an aggregation of α-synuclein (αSyn). In LBD, not only the sole aggregation of αSyn but also the co-aggregation of amyloidogenic proteins, such as amyloid-β (Aβ) and tau, has been reported. In this review, the pathophysiology of co-aggregation of αSyn, Aβ, and tau protein and the advancement in imaging and fluid biomarkers that can detect αSyn and co-occurring Aβ and/or tau pathologies are discussed. Additionally, the αSyn-targeted disease-modifying therapies in clinical trials are summarized.

The emerging double-edged sword role of exosomes in Alzheimer's disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by progressive loss of memory and cognitive dysfunction. The primary pathological hallmarks of AD are senile plaques formed by deposition of amyloid β (Aβ) protein, intracellular neurofibrillary tangles resulting from hyperphosphorylation of microtubule-associated protein tau, and loss of neurons. At present, although the exact pathogenesis of AD is still unclear and there is a lack of effective treatment for AD in clinical practice, researchers have never stopped exploring the pathogenic mechanism of AD. In recent years, with the rise of the research of extracellular vesicles (EVs), people gradually realize that EVs also play important roles in neurodegenerative diseases. Exosomes, as a member of the small EVs, are regarded as carriers for information exchange and material transport between cells. Many cells of the central nervous system can release exosomes in both physiological and pathological conditions. Exosomes derived from damaged nerve cells can not only participate in Aβ production and oligomerization, but also disseminate the toxic proteins of Aβ and tau to neighboring neurons, thereby acting as "seeds" to amplify the toxic effects of misfolded proteins. Furthermore, exosomes may also be involved in the degradation and clearance process of Aβ. There is increasing evidence to suggest that exosomes play multiple roles in AD. Just like a double-edged sword, exosomes can participate in AD pathology in a direct or indirect way, causing neuronal loss, and can also participate in alleviating the pathological progression of AD. In this review, we summarize and discuss the current reported research findings on this double-edged role of exosomes in AD.

Peptide-Functionalized Prussian Blue Nanomaterial for Antioxidant Stress and NIR Photothermal Therapy against Alzheimer's Disease.

Excessive accumulations of reactive oxygen species (ROS) and amyloid-β (Aβ) protein are closely associated with the complex pathogenesis of Alzheimer's disease (AD). Therefore, approaches that synergistically exert elimination of ROS and dissociation of Aβ fibrils are effective therapeutic strategies for correcting the AD microenvironment. Herein, a novel near infrared (NIR) responsive Prussian blue-based nanomaterial (PBK NPs) is established with excellent antioxidant activity and photothermal effect. PBK NPs possess similar activities to multiple antioxidant enzymes, including superoxide dismutase, peroxidase, and catalase, which can eliminate massive ROS and relieve oxidative stress. Under the NIR irradiation, PBK NPs can generate local heat to disaggregate Aβ fibrils efficiently. By modifying CKLVFFAED peptide, PBK NPs display obvious targeting ability for blood-brain barrier penetration and Aβ binding. Furthermore, in vivo studies demonstrate that PBK NPs have outstanding ability to decompose Aβ plaques and alleviate neuroinflammation in AD mouse model. Overall, PBK NPs provide evident neuroprotection by reducing ROS levels and regulating Aβ deposition, and may accelerate the development of multifunctional nanomaterials for delaying the progression of AD.

A computational framework for identifying chemical compounds to bind Apolipoprotein E4 for Alzheimer’s disease intervention

Alzheimer’s disease (AD), a neurodegenerative disorder, is characterized by its ability to cause memory loss and damage other cognitive functions. Aggregation of amyloid beta (Aβ) plaques and neurofibrillary tangles in the brain are responsible for the development of Alzheimer’s disease (AD). While attempts targeting Aβ and tau proteins have been extensively conducted in the past decades, only two FDA-approved drugs (i.e., monoclonal antibodies) tackle the underlying biology of Alzheimer’s disease. In this study, an integrated computational framework was developed to identify new drug targets for Alzheimer’s disease and identify small molecules as potential therapeutical options. A systematic investigation of the gene networks firstly revealed that the Apolipoprotein E4 (ApoE4) gene plays a central role among genes associated with Alzheimer’s disease. The ApoE4 protein was then chosen as the protein target based on its role in the main pathological hallmarks of AD, which has been shown to increase Aβ accumulation by directly binding to Aβ as well as interfering with Aβ clearance that is associated with other receptors. A library of roughly 1.5 million compounds was then virtually screened via a ligand-protein docking program to identify small-molecule compounds with potential binding capacity to the ApoE4 N-terminal domain. On the basis of compound properties, 312 compounds were selected, analyzed and clustered to further identify common structures and essential functional groups that play an important role in binding ApoE4. The in silico prediction suggested that compounds with four common structures of sulfon-amine-benzene, 1,2-benzisothiazol-3-amine 1,1-dioxide, N-phenylbenzamide, and furan-amino-benzene presented strong hydrogen bonds with residues E27, W34, R38, D53, D153, or Q156 in the N terminal of ApoE4. These structures might also form strong hydrophobic interactions with residues W26, E27, L28, L30, G31, L149, and A152. While the 312 compounds can serve as drug candidates for further experiment assays, the four common structures, along with the residues for hydrogen bond or hydrophobic interaction, pave the foundation to further optimize the compounds as better binders of ApoE4.

Metal mixture-induced non-transgenic animal model of Alzheimer’s disease: Pros and cons

Alzheimer’s disease (AD) is a multifaceted and heterogeneous age-related disease and represents the most common cause of dementia among the elderly. Over the past two decades, transgenic models of AD appreciably contribute to the understanding of the molecular mechanisms involved in the onset and progression of AD. However, transgenic models generally identify with the familial form of AD that accounts for just 5% of AD cases. Thus, non-transgenic models are also essential to thoroughly understand AD pathophysiology. Environmental exposure to heavy metals has been linked to the pathogenesis of the non-familial, sporadic form of AD. This review summarizes our previously published research that showed a mixture of heavy metals, i.e. Arsenic (As), cadmium (Cd) and lead (Pb) at environmentally relevant doses induced AD-parameters and AD-like pathology in the young rats. Our previous findings suggest that the amyloid beta-42 (Aβ1-42) levels in the As+Cd+Pbmixture treated Postnatal-90 day rat brain were comparable with the intracerebroventricular Aβ1-42 infusion rat model, which is well- established non-transgenic model of AD. Additionally, As+Cd+Pb-mixtureinduced Aβ and amyloid precursor protein could be attenuated by known AD-directed drugs, memantine, and donepezil. These findings helped us to conclude that As+Cd+Pb-treated animals could be utilized as a non-transgenic model of AD. This review also summarizes the merits of a nontransgenic animal model of AD, generated through environmental doses of As, Cd and Pb-mixture and its demerits.

Shenqi formula delayed Alzheimer’s disease-like symptoms by skn-1 pathway in Caernorhabditis elegans

Ethnopharmacological relevanceShenqi formula is composed of Codonopsis pilosula (Cp) and Lycium barbarum (Lb), and it is traditionally used for promoting qi and nourishing the spleen, liver and kidney. Cp and Lb have been reported to improve cognitive performance in APP/PS1 mice, prevent the accumulation of Aβ, and reduce the neurotoxicity of Aβ to achieve the anti-Alzheimer's disease (AD) effect. Aim of the studyShenqi formula was explored the therapeutic effect on Caenorhabditis elegans AD pathological model and the underlying mechanism of action. Materials and methodsParalysis assay and serotonin sensitivity assay was used to detect whether Shenqi formula can alleviate AD paralysis phenotype, and then DPPH, ABTS, NBT and Fenton methods were applied to investigate the scavenging capacity to free radical, ROS, ·O2− and ·OH of Shenqi formula in vitro. H2DCF-DA and MitoSOX™ Red were employed to measure ROS and .O2− accumulation, respectively. RNAi was used to knock down the expression of skn-1 and daf-16 related to oxidative stress resistance signalling pathway. Fluorescence microscopy was used to record the expression of SOD-3::GFP, GST-4::GFP, SOD-1::YFP, and the nuclear translocation of SKN-1 and DAF-16. Western blot assay was carried out to test Aβ monomers and oligomers. ResultsShenqi formula delayed the AD-like pathological characteristics in C. elegans, and the complete Shenqi formula was more effective than Cp or Lb alone. The effect of Shenqi formula on delaying worm paralysis was partially eliminated by skn-1 RNAi, but not daf-16 RNAi. Shenqi formula significantly inhibited the abnormal deposition of Aβ protein, decreased Aβ protein monomers and oligomers. It increased the expressions of gst-4, sod-1, and sod-3 similar to paraquat, companied by rise then fall of ROS and .O2− in AD worms. ConclusionsShenqi formula at least partially depended on SKN-1 signalling pathway to exert its anti-AD effect, and it is potential to be used as a kind of health food to prevent the progress of AD.

Alzheimer's disease: A role of biomarkers in early diagnosis and evidences from African ethnomedicinal knowledge.

Alzheimer's disease (AD) is a neurological ailment that primarily affects the elderly and necessitates an efficient treatment regimen backed up by extensive care. Despite advancement in the in vivo imaging techniques focussing on early diagnosis of reliable biomarkers using novel magnetic resonance imaging (MRI) and positron emission topography (PET) scans, AD remains largely unexplained and effective preventative and treatment strategies are still lacking. Consequently, research groups are constantly attempting to improve its early detection, using both invasive and non-invasive techniques with established core markers like Aβ and Tau (t-tau and p-tau) proteins. Unfortunately, African American and other black races are facing an increasing burden of closely associated risk factors, and only a few attempts have been made to find effective complementary and alternative therapies for AD cure and management. A greater epidemiology and natural product research are required to deal with the concurrent rise of dementia among quickly ageing African population, which so far have largely been ignored in addition to a disparity in the AD risk factors. We have tried to bring attention to the issue by reviewing up on this predisposition while generating a perspective on how race may affect AD risk and expression. This article also puts emphasis on finding new research leads from African phytodiversity while presenting several of the important species along with their biological agents found helpful in dementia related symptoms.

Neuronal ApoE4 in Alzheimer's disease and potential therapeutic targets.

The most prevalent genetic risk factor for Alzheimer's disease (AD) is Apolipoprotein E (ApoE), a gene located on chromosome 19 that encodes three alleles (e2, e3, and e4) that give rise to the ApoE subtypes E2, E3, and E4, respectively. E2 and E4 have been linked to increased plasma triglyceride concentrations and are known to play a critical role in lipoprotein metabolism. The prominent pathological features of AD mainly include senile plaques formed by amyloid β (Aβ42) aggregation and neuronal fibrous tangles (NFTs), and the deposited plaques are mainly composed of Aβ hyperphosphorylation and truncated head. In the central nervous system, the ApoE protein is primarily derived from astrocytes, but ApoE is also produced when neurons are stressed or affected by certain stress, injury, and aging conditions. ApoE4 in neurons induces Aβ and tau protein pathologies, leading to neuroinflammation and neuronal damage, impairing learning and memory functions. However, how neuronal ApoE4 mediates AD pathology remains unclear. Recent studies have shown that neuronal ApoE4 may lead to greater neurotoxicity, which increases the risk of AD development. This review focuses on the pathophysiology of neuronal ApoE4 and explains how neuronal ApoE4 mediates Aβ deposition, pathological mechanisms of tau protein hyperphosphorylation, and potential therapeutic targets.

Amyloid accumulation and functional connectivity in normal aging and preclinical Alzheimer’s Disease: a longitudinal analysis of the OASIS‐3 cohort

AbstractBackgroundPathological changes in the brain begin accumulating decades before the appearance of cognitive symptoms in Alzheimer’s Disease (AD). The deposition of amyloid‐beta (Aβ) proteins and other neurotoxic changes occur, leading to disruption in functional connections between brain networks. Discrete characterization of the changes that take place in preclinical AD has the potential to help treatment development by targeting the neuropathological mechanisms to prevent cognitive decline and dementia from occurring entirely. Previous research has focused on cross sectional differences in the brains of patients with mild cognitive impairment (MCI) or AD and healthy controls or has concentrated on the stages immediately preceding cognitive symptoms. The present study emphasizes early preclinical phases of neurodegeneration.MethodWe use a longitudinal approach to examine the brain changes that take place during early stages of cognitive decline in the OASIS‐3 dataset. Among 1098 participants, 274 passed the inclusion criteria (i.e. had at least two repeated measures of cognitive status and amyloid levels). We use mixed‐effect linear models to examine rates of amyloid accumulation in those who showed cognitive decline compared to those who did not change in cognitive status.ResultOver 90% of participants were healthy at baseline. Over 8‐10 years, some participants progressed to very mild dementia (n = 48) while others stayed healthy (n = 226). Participants with cognitive decline have faster amyloid accumulation and greater increases in functional connectivity in similar brain regions, namely among lateral temporal, motor, and some lateral prefrontal cortex areas. These changes were linked to increases in functional connectivity of select default mode, frontoparietal and motor components.ConclusionOur findings advance the understanding of initial amyloid staging in preclinical Alzheimer’s, as well as contribute to the determination of the functional changes that occur among brain network components as the disease progresses.