Against Alzheimer's Disease Research Articles

Current Anti-Amyloid-β Therapy for Alzheimer's Disease Treatment: From Clinical Research to Nanomedicine.

Recent successive approval of anti-amyloid-β (Aβ) monoclonal antibodies as disease-modifying therapies against Alzheimer's disease (AD) has raised great confidence in the development of anti-AD therapies; however, the current therapies still face the dilemma of significant adverse reactions and limited effects. In this review, we summarized the therapeutic characteristics of the approved anti-Aβ immunotherapies and dialectically analyzed the gains and losses from clinical trials. The review further proposed the reasonable selection of animal models in preclinical studies from the perspective of different animal models of Aβ deposition and deals in-depth with the recent advances of exploring preclinical nanomedical application in Aβ targeted therapy, aiming to provide a reliable systematic summary for the development of novel anti-Aβ therapies. Collectively, this review comprehensively dissects the pioneering work of Aβ-targeted therapies and proposed perspective insight into AD-modified therapies.

Kamikihito reduces β-amyloid25-35-induced axon damage via neurotrophic factors.

The Japanese herbal medicine kamikihito (KKT) is widely used for insomnia, anorexia, anemia, and depression. Recently, the efficacy of KKT against Alzheimer's disease (AD) has been demonstrated in clinical and non-clinical studies. To address the mechanism underlying the effect of KKT on AD, we examined the effects of KKT in β-amyloid (Aβ)25-35-exposed primary cultured neurons. The effects of KKT on Aβ25-35-induced neurotoxicity were assessed by immunocytochemical assays and Sholl analysis of neurites, and the influence of KKT on neurotrophic factor (NF) gene expression was examined using RT-PCR analysis. As a result, Aβ25-35 exposure attenuated the arborization of neurites of single cultured hippocampal neurons, and KKT treatment for 3days ameliorated the Aβ25-35-induced impairment of tau-positive axon outgrowth. This ameliorative effect of KKT was largely abolished by the Trk inhibitor K252a, and expression of NFs, nerve growth factor (Ngf), brain-derived neurotrophic factor (Bdnf), neurotrophin-3 (NT-3) was significantly increased by KKT. These results indicate that KKT ameliorates axonal atrophy via NFs signaling, providing a mechanistic basis for treatment of AD with KKT.

Computational screening of foxtail millet (Setaria italica (L.) P.Beauv.) polyphenols for finding β-secretase (BACE 1) inhibitors that target the amyloidogenic pathway in Alzheimer's disease

Abstract BACKGROUND: Foxtail millet (FM; Setaria italica (L.) P.Beauv.) is known for its antioxidant and neuroprotective action against Alzheimer's disease (AD); hence the present study aims to screen its polyphenols to find less toxic and potentially effective anti-Alzheimer's drugs. MATERIALS AND METHODS: The details about phyto-compounds of FM and the β-secretase enzyme (BACE 1) of AD have been retrieved from the PubChem compound database and protein data bank, respectively. The Patch Dock server was used to carry out docking experiments. Initially, all the FM phytocompounds and reference drug (MK-8931) were subjected to docking, and subsequently, the best-docked complexes were selected based on their binding energy (in kcal/mol). Rule of five and adsorption, distribution, metabolism, excretion, and toxicity (ADMET) of selected compounds were analyzed using various computational tools. The final docking complexes were developed by using PyMOL. RESULTS: The molecular docking results revealed that among the 24 polyphenols studied, two compounds, namely N′-p-coumaroyl-N″-caffeoylspermidine (NPCNCS) and di-P-coumaroylspermidine (DPCS), demonstrated strong binding to the active site of β-secretase. and exhibited higher binding energies of -300.75 kcal/mol and -193.41 kcal/mol, respectively, in comparison to the reference drug MK-8931, with a binding energy of -154.36 kcal/mol. These compounds established hydrogen bond interactions with catalytic dyad (Asp 32 and Asp 228) and other accessory interactions with residues of the “flap” hairpin loop and “10s loop” of the β-secretase active site involved in the stabilization of substrate/inhibitor binding. In a nutshell, the NPCNCS and DPCS have shown more robust binding affinity than MK-8931 and docked well into the interior side of the active site. On the other hand, NPCNCS and DPCS have satisfied the RO5 and ADMET filters. CONCLUSIONS: The in silico analysis of FM polyphenols revealed that the N′-p-coumaroyl-N″-feruloylspermidine and di-P-coumaroylspermidine compounds exhibited non-toxic, permeability to blood-brain barrier and solid binding affinity toward β-secretase enzyme thereby; these millet compounds might be considered as β-secretase inhibitors for treating AD.

Exploring Multitarget Strategies for Membrane Protection in Alzheimer's Disease.

The exploration of multitarget molecules presents a promising avenue in the quest for effective therapeutic strategies against Alzheimer's disease (AD), a multifactorial neurodegenerative disorder. Traditional single-target drugs have shown limited success due to the complex interplay of pathological processes involved in AD. Multitarget-directed ligands (MTDLs), designed to interact with multiple targets simultaneously, offer a more holistic approach to address the multifaceted nature of neurodegenerative diseases. Recent studies have highlighted the potential of chalcones and huprine derivatives in mitigating amyloid-β peptide-associated toxicity and preserving membrane integrity, crucial for cellular homeostasis. The interaction of these compounds with lipid bilayers may modulate biological responses, opening a new realm of investigation in membrane-centric phenomena. This approach not only broadens the mechanistic understanding of bioactive compounds but also underscores the need for a paradigm shift in AD research, focusing on both intracellular targets and plasma membrane protection for more effective treatment strategies.

Abl depletion via autophagy mediates the beneficial effects of quercetin against Alzheimer pathology across species

Alzheimer’s disease is the most common age-associated neurodegenerative disorder and the most frequent form of dementia in our society. Aging is a complex biological process concurrently shaped by genetic, dietary and environmental factors and natural compounds are emerging for their beneficial effects against age-related disorders. Besides their antioxidant activity often described in simple model organisms, the molecular mechanisms underlying the beneficial effects of different dietary compounds remain however largely unknown. In the present study, we exploit the nematode Caenorhabditis elegans as a widely established model for aging studies, to test the effects of different natural compounds in vivo and focused on mechanistic aspects of one of them, quercetin, using complementary systems and assays. We show that quercetin has evolutionarily conserved beneficial effects against Alzheimer’s disease (AD) pathology: it prevents Amyloid beta (Aβ)-induced detrimental effects in different C. elegans AD models and it reduces Aβ-secretion in mammalian cells. Mechanistically, we found that the beneficial effects of quercetin are mediated by autophagy-dependent reduced expression of Abl tyrosine kinase. In turn, autophagy is required upon Abl suppression to mediate quercetin’s protective effects against Aβ toxicity. Our data support the power of C. elegans as an in vivo model to investigate therapeutic options for AD.

MAO-B Inhibitor (2E)-3-(4-Bromophenyl)-1-(1H-indol-3-yl) prop-2-en-1-one as a Neuroprotective Agent Against Alzheimer's Disease.

Chalcones (trans-1,3-diphenyl-2-propen-1-ones) form simple chemical structures that act as precursors for the biogenesis of flavonoids. These are distributed in plants and have two aromatic or heteroaromatic rings connected by a three-carbon α, β-unsaturated carbonyl group. Considering the importance of chalcones as monoamine oxidase and acetylcholinesterase inhibitors, the study was designed as a comprehensive and systematic analysis to evaluate the pharmacological activities leading to the formation of drug molecules against Alzheimer's disease (AD). Based on our previous research, 11 indolyl chalcones (IC1-IC11) were synthesised and investigated for MAO-B inhibitory activity. The inhibitory potential was evaluated based on binding and reversibility studies using purified enzymes. The active and most promising molecule, (2E)-3-(4-bromophenyl)-1-(1H-indol-3-yl) prop-2-en-1-one (IC9), also found predominant acetylcholinesterase inhibition and hence it was found dual acting in vitro. Based on this, the molecule IC9 was further subjected to cell line studies to further explore its role as a neuroprotective agent against neuronal degeneration, one of the main contributing parameters related to AD.

Blueberry extracts antagonize Aβ25–35 neurotoxicity and exert a neuroprotective effect through MEK-ERK-BDNF/UCH-L1 signaling pathway in rat and mouse hippocampus

ABSTRACT Background The neuroprotective potential of blueberry (BB) extracts against Alzheimer's disease (AD) has been previously hinted at, while its exact mechanism has remained largely enigmatic. Objective Our study endeavored to unravel the impacts and mechanisms by which BB extracts ameliorated the learning and memory prowess of AD-afflicted mice, with a specific focus on the MEK-ERK pathway. Methods We employed 3-month-old APP/PS1 transgenic mice and stratified them into three distinct groups: AD+BB, AD, and control (CT). The Morris Water Maze Test (MWMT) was then administered to gauge their learning and memory faculties. In vitro experiments were executed on Aβ25-35-afflicted rat hippocampal neurons, which were subsequently treated with varying concentrations of BB extracts. We then assessed the expression levels of genes and proteins integral to the MEK-ERKBDNF/UCH-L1 pathway. Results The data showed that the AD mice demonstrated compromised learning and memory faculties in MWMT. However, the AD+BB cohort showcased marked improvements in performance. Furthermore, in the AD subset, significant elevations in the expressions of MEK2 and ERK1/2 were observed, both at the mRNA and protein levels. Conversely, UCH-L1 mRNA expressions exhibited a decline, while BDNF expressions surged significantly. However, post BB extract treatment, the expressions of MEK2 and ERK1/2 were subdued, with UCH-L1 and BDNF mRNA expressions reverting to control levels. Conclusions Our findings propounded that BB extracts could offer therapeutic promise for AD by bolstering learning and memory capacities. The unwarranted activation of the MEK-ERK pathway, coupled with the aberrant expressions of BDNF and UCH-L1, might underpin AD's pathogenesis.

Hyperoside Prevents Aβ42-Induced Neurotoxicity in PC12 Cells and Caenorhabditis elegans.

Traditional Chinese medicines such as hyperoside-rich Acanthopanax senticosus and Crataegus pinnatifida have been confirmed to exhibit anti-oxidative stress properties. Hyperoside, the main ingredient of numerous antioxidant herbs, may have the ability to postpone the onset of neurodegenerative diseases. This study investigates the possible therapeutic mechanism of hyperoside as a natural antioxidant against Alzheimer's disease (AD) in Caenorhabditis elegans and PC12 cells. Specifically, hyperoside reduced reactive oxygen species (ROS) level and Aβ42-induced neurotoxicity in C. elegans worms. Meanwhile, hyperoside reduced ROS production and increased mitochondrial membrane potentialin Aβ42-induced PC12 cells, which possibly due to the increase of antioxidant enzymes activity and the diminution of malondialdehyde levels. Hoechst 33,342 staining and flow cytometry analysis results suggested that hyperoside reverses cell apoptosis. Network pharmacology predicts potentially relevant hyperoside targets and pathways in AD therapy. As anticipated, hyperoside reversed Aβ42-stimulated downregulation of the PI3K/Akt/Nrf2/HO-1. The PI3K inhibitor LY294002 partially abolished the protective capability of hyperoside. The results of molecular docking further indicated that the PI3K/Akt pathways may be involved in the protection of Aβ42-induced PC12 cells by hyperoside treatment. The study provides theoretical information for research and development of hyperoside as an antioxidant dietary supplement.

Prevailing Antagonistic Risks in Pleiotropic Associations with Alzheimer's Disease and Diabetes.

The lack of efficient preventive interventions against Alzheimer's disease (AD) calls for identifying efficient modifiable risk factors for AD. As diabetes shares many pathological processes with AD, including accumulation of amyloid plaques and neurofibrillary tangles, insulin resistance, and impaired glucose metabolism, diabetes is thought to be a potentially modifiable risk factor for AD. Mounting evidence suggests that links between AD and diabetes may be more complex than previously believed. To examine the pleiotropic architecture of AD and diabetes mellitus (DM). Univariate and pleiotropic analyses were performed following the discovery-replication strategy using individual-level data from 10 large-scale studies. We report a potentially novel pleiotropic NOTCH2 gene, with a minor allele of rs5025718 associated with increased risks of both AD and DM. We confirm previously identified antagonistic associations of the same variants with the risks of AD and DM in the HLA and APOE gene clusters. We show multiple antagonistic associations of the same variants with AD and DM in the HLA cluster, which were not explained by the lead SNP in this cluster. Although the ɛ2 and ɛ4 alleles played a major role in the antagonistic associations with AD and DM in the APOE cluster, we identified non-overlapping SNPs in this cluster, which were adversely and beneficially associated with AD and DM independently of the ɛ2 and ɛ4 alleles. This study emphasizes differences and similarities in the heterogeneous genetic architectures of AD and DM, which may differentiate the pathogenic mechanisms of these diseases.

Computational Evaluation of Azadirachta indica-Derived Bioactive Compounds as Potential Inhibitors of NLRP3 in the Treatment of Alzheimer's Disease.

The development of therapeutic agents against Alzheimer's disease (AD) has stalled recently. Drug candidates targeting amyloid-β (Aβ) deposition have often failed clinical trials at different stages, prompting the search for novel targets for AD therapy. The NLRP3 inflammasome is an integral part of innate immunity, contributing to neuroinflammation and AD pathophysiology. Thus, it has become a promising new target for AD therapy. The study sought to investigate the potential of bioactive compounds derived from Azadirachta-indica to inhibit the NLRP3 protein implicated in the pathophysiology of AD. Structural bioinformatics via molecular docking and density functional theory (DFT) analysis was utilized for the identification of novel NLRP3 inhibitors from A. indica bioactive compounds. The compounds were further subjected to pharmacokinetic and drug-likeness analysis. Results obtained from the compounds were compared against that of oridonin, a known NLRP3 inhibitor. The studied compounds optimally saturated the binding site of the NLRP3 NACHT domain, forming principal interactions with the different amino acids at its binding site. The studied compounds also demonstrated better bioactivity and chemical reactivity as ascertained by DFT analysis and all the compounds except 7-desacetyl-7-benzoylazadiradione, which had two violations, conformed to Lipinski's rule of five. In silico studies show that A. indica derived compounds have better inhibitory potential against NLRP3 and better pharmacokinetic profiles when compared with the reference ligand (oridonin). These compounds are thus proposed as novel NLRP3 inhibitors for the treatment of AD. Further wet-lab studies are needed to confirm the potency of the studied compounds.

Computational Fragment-Based Design of Phytochemical Derivatives as EGFR Inhibitors.

Epidermal growth factor receptor (EGFR) is a potential target with disease modifying benefits against Alzheimer's disease (AD). Repurposing of FDA approved drugs against EGFR have shown beneficial effect against AD but are confined to quinazoline, quinoline and aminopyrimidines. Futuristically, the possibility of acquiring drug resistance mutation as seen in the case of cancer could also hamper AD treatment. To identify novel chemical scaffolds, we rooted on phytochemicals identified from plants such as Acorus calamus, Bacopa monnieri, Convolvulus pluricaulis, Tinospora cordifloia, and Withania somnifera that have well-established records in the treatment of brain disorders. The rationale was to mimic the biosynthetic metabolite extension process observed in the plants for synthesizing new phytochemical derivates. Thus, novel compounds were designed computationally by fragment-based method followed by extensive in silico analysis to pick potential phytochemical derivates. PCD1, 8 and 10 were predicted to have better blood brain barrier permeability. ADMET and SoM analysis suggested that these PCDs exhibited druglike properties. Further simulation studies showed that PCD1 and PCD8 stably interact with EGFR and have the potential to be used even in cases of drug-resistance mutations. With further experimental evidence, these PCDs could be leveraged as potential inhibitors of EGFR.

Quinolinetrione-tacrine hybrids as multi-target-directed ligands against Alzheimer's disease

Multi-target drug discovery is one of the most active fields in the search for new drugs against Alzheimer's disease (AD). This is because the complexity of AD pathological network might be adequately tackled by multi-target-directed ligands (MTDLs) aimed at modulating simultaneously multiple targets of such a network. In a continuation of our efforts to develop MTDLs for AD, we have been focusing on the molecular hybridization of the acetylcholinesterase inhibitor tacrine with the aim of expanding its anti-AD profile. Herein, we manipulated the structure of a previously developed tacrine-quinone hybrid (1). We designed and synthesized a novel set of MTDLs (2–6) by replacing the naphthoquinone scaffold of 1 with that of 2,5,8-quinolinetrione. The most interesting hybrid 3 inhibited cholinesterase enzymes at nanomolar concentrations. In addition, 3 exerted antioxidant effects in menadione-induced oxidative stress of SH-SY5Y cells. Importantly, 3 also showed low hepatotoxicity and good anti-amyloid aggregation properties. Remarkably, we uncovered the potential of the quinolinetrione scaffold, as a novel anti-amyloid aggregation and antioxidant motif to be used in further anti-AD MTDL drug discovery endeavors.

Association between physical activity and episodic memory and the moderating effects of the apolipoprotein E ε4 allele and age.

An abundance of evidence indicates that physical activity may protect against Alzheimer's disease (AD) and related cognitive decline. However, little is known about the association between physical activity and AD-related cognitive decline according to age and the apolipoprotein E (APOE) ε4 allele (APOE4) as major risk factors. Therefore, we examined whether age and APOE4 status modulate the effects of physical activity on episodic memory as AD-related cognition in non-demented older adults. We enrolled 196 adults aged between 65 and 90 years, with no dementia. All participants underwent comprehensive clinical assessments including physical activity evaluation and APOE genotyping. The AD-related cognitive domain was assessed by the episodic memory, as the earliest cognitive change in AD, and non-memory cognition for comparative purposes. Overall cognition was assessed by the total score (TS) of the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological battery. We found significant physical activity × age and physical activity × APOE4 interaction effects on episodic memory. Subgroup analyses indicated that an association between physical activity and increased episodic memory was apparent only in subjects aged > 70 years, and in APOE4-positive subjects. Our findings suggest that physical activity has beneficial effects on episodic memory, as an AD-related cognitive domain, in individuals aged > 70 years and in APOE4-positive individuals. Physicians should take age and APOE4 status account into when recommending physical activity to prevent AD-related cognitive decline.

Attempts to Develop Vaccines Against Alzheimer's Disease: A Systematic Review of Ongoing and Completed Vaccination Trials in Humans.

In this systematic review, we evaluate the safety, tolerability, and immunogenicity of vaccination efforts against Alzheimer's disease (AD) in human subjects from both ongoing and completed vaccination trials. Databases like PubMed, Embase, and Scopus were used to identify relevant articles on completed vaccination trials whereas the clinicaltrials.gov database was used for identifying ongoing clinical trials for vaccination against AD in humans until January 2022. Only interventional randomized or non-randomized clinical trials which reported on the safety and immunogenicity of vaccine against AD in humans were included. Cochrane risk of bias tool-2 (RoB-2) or risk of bias in non-randomized studies- of intervention (ROBINS-I) was used for risk of bias assessment as appropriate. A narrative descriptive synthesis of the findings was done. Sixteen randomized/non-randomized clinical trials (phase I: six and phase II: 10) for seven different types of vaccines against AD were identified comprising a total of 2080 participants. Apart from the development of meningoencephalitis in 6% of patients receiving AN1792 in an interrupted phase II trial, the rest of the trial reported promising results on the safety and immunogenicity of vaccines. While only a subset of reported adverse events was treatment related, none of the fatalities reported during the trial were considered related to vaccine administration. The serological response rate ranged from 100% (4/16 trials) to 19.7% in an interrupted trial. Although current trials show promising results, adequately powered phase III studies are needed to conclusively establish the safety, immunogenicity and therapeutic efficacy of vaccines.

Neuroprotective effects of Cubebin and Hinokinin lignan fractions of Piper cubeba fruit in Alzheimer’s disease in vitro model

Abstract Objectives The current research examines the protective effects of the Piper cubeba ethanolic extract and its isolated lignans; Cubebin and Hinokinin fractions against Alzheimer’s Disease (AD) in vitro model. Methods Dried and powdered fruit of P. cubeba were extracted in ethanol and fractionated using silica gel column chromatography. Of the 15 eluted fractions, two fractions indicated presence of targeted Lignans; Hinokinin and Cubebin. They were monitored by thin layered chromatography and their structures were confirmed by LC-HRMS spectrometry and NMR analysis. Antioxidant activity of the crude extract and isolated lignan fractions were analyzed using FRAP, DPPH and ABTS assays. Anti-acetylcholinesterase activity was investigated in vitro and β-amyloid (Aβ) cytotoxicity on SHSY-5Y human neuroblastoma cell lines was studied using MTT assay. Results The crude extract showed similar if not significantly stronger antioxidant capacity compared to ascorbic acid in FRAP and DPPH assays. Both lignans exerted weaker yet potent activity. The crude extract yielded the strongest acetylcholinesterase inhibitory potential compared to the lignan fractions however, there was no significant difference (p<0.05) between IC50 values of lignan fractions. Significant neuroprotective effects against 50 μM Aβ at p<0.05 was observed for selected fractions compared to Aβ treated control. The crude extract was highly protective against Aβ at both 5 and 10 μg/mL. Cubebin and Hinokinin-containing fractions significantly improved the viability of the SH-SY5Y cells against Aβ cytotoxicity both only at the concentration of 100 μg/mL. Conclusions Results from our studies suggest that these phytoconstituents might be good candidates in prevention and treatment of AD.

The impact of dance‐movement interventions on psychological health in older adults: A systematic review and meta‐analysis of randomized controlled trials

AbstractBackgroundGood psychological health is proposed as a key factor in the protection against Alzheimer’s disease (AD) and age‐related cognitive decline1. Multimodal motor, cognitive, sensory, and social enrichment as induced by dance‐movement interventions (DMI) could promote psychological health in the older population. This systematic review and meta‐analysis investigated the impact of DMI compared to control intervention (active/passive) on psychological health in older adults.MethodsA systematic search of three databases (PubMed, Web of Science, PsycInfo; screenings: April and November 2021) was conducted following PRISMA guidelines. Criteria included randomized controlled trials (RCTs) evaluating the effects of DMI (minimum 4 weeks’ duration) on health‐related psychological outcomes (primary outcome) and global cognitive functioning (secondary outcome) among non‐demented older adults (≥ 55 years of age). A random‐effects meta‐analysis with robust variance estimation was carried out. This review was registered with PROSPERO (CRD42021265112).ResultsData of 13 eligible primary RCTs (n = 943, n‐DMI = 474, n‐control = 469) were synthesized. Overall heterogeneity of results and risk of bias across RCTs were high. DMI had a small positive impact on psychological health compared to control (g = 0.31; 95% Confidence Interval (CI): [0.09, 0.53]; p = .01, I2 = 62.55). Separation of psychological health into positive and negative outcomes and particularly social and emotional aspects showed similar trends favouring DMI compared to control (see Figure 1). Analysis of secondary outcomes indicated a positive effect of DMI on global cognitive functioning (g = 0.48; 95%CI: [0.03, 0.93], p = .04, I2 = 82.44). Exploratory subgroup analyses suggested that the implementation of longer intervention durations and psychotherapeutic elements increase the psychological health benefits of DMI.ConclusionMultimodal interventions, as specifically offered by DMI, may serve as an effective tool to promote psychological health together with cognitive functioning in older adults. High‐quality future trials are needed to expand evidence on the particular aspects of psychological health and identify underlying neurophysiological correlates. We will present a protocol for a prospective RCT to assess the impact of a DMI on psychological, cognitive and brain health outcomes in the older population at increased risk of AD.References1Livingston G, et al. Lancet 2020.

Executive function may underlie cognitive reserve: A 3‐year follow‐up study

AbstractBackgroundThe hypothetical concept of cognitive reserve (CR) has been proposed to explain why someone can manage to function normally even in the presence of brain pathology. However, it still remains to be determined what components constitute such resilience against Alzheimer’s disease (AD) pathology. In the current study we investigated the characteristics of cognitively normal (CN) elders with high CR.MethodWe included CN participants from the Gwangju Alzheimer’s Disease and Related Dementia Cohort in Korea. We selected a group of CN individuals who showed a significant amyloid‐beta (aß) deposition at baseline and stayed CN over the follow‐up period. They were defined as high CR group. For comparison purpose, individuals with a significant aß deposition at baseline but converted to MCI at follow‐up were also included. In the final analysis, 94 high CR group and 24 control group were included. Group comparisons in socio‐demographic, clinical and cognitive variables were performed using χ2 tests and ANOVA controlling for age, education, gender, and follow‐up month.ResultMean follow‐up month were 43.37. There were no group differences in education, gender, socio‐economic status, family history of dementia or stroke, medical conditions, body mass index, subjective memory complaints, and instrumental activities of daily living. However, high CR group was younger and had shorter follow‐up period, therefore such variables were controlled when cognitive tests were compared. High CR group was more religious (p < 0.001), showed higher complexity in former job (p = 0.009), and higher level of executive functoning (Digit Dpan Backward, p = 0.012; Fluency test, p = 0.008; Boston Naming Test, p = 0.014; Trail Making Test part B, p = 0.017) than control group. There were no group differences in episodic memory tests and visuospatial abilities.ConclusionIndividuals with high CR could cope better with AD pathology. Many factors have been suggested to be associated with CR. Regarding cognitive process involved, our findings suggest that executive function plays an important role in constituting high CR. Preserved executive function may, at least in part, underlie CR.

Organosilane as a versatile compound: Silica-Based nanoparticles for detection of methyl parathion and inhibition of acetylcholinesterase (AChE) in Alzheimer’s disease

In this article, we sketched and synthesized chalcone appended triazole organosilane (TP), and it was thoroughly characterised using NMR (1H and 13C) and mass spectrometry. Furthermore, TP was immobilized over the silica nanoparticles (TP-NPs) utilizing one-pot strategy, and TP-NPs were thoroughly characterised using various techniques including FT-IR, XRD, EDX, FE-SEM, and TGA. TP-NPs were found to be very sensitive and selective towards detection of methyl parathion (MP) over other tested ions by both UV–Visible and fluorescence spectroscopy, with values of limit of detection as low as 3.83 X 10−9 M and 5.76 X 10−10 M, respectively. TP-NPs has high surface area and have various functional group present on the surface which aid in the detection of MP; nitrogens of the triazole moiety have high affinity for phosphorous atom in MP while Si atom interacts with the oxygen present in the MP, facilitating the sensing of MP by TP-NPs. Additionally, in silico docking studies showed that TP exhibits a good inhibitory response to the human acetylcholinesterase (AChE) protein, making it a potential candidate against Alzheimer’s disease (AD). Also, the real sample analyses of methyl parathion in agricultural soil and water samples were successfully done with excellent recovery rates, ranging from 92.25% to 109%, respectively.

Protective Alzheimer's disease-associated APP A673T variant predominantly decreases sAPPβ levels in cerebrospinal fluid and 2D/3D cell culture models

The rare A673T variant was the first variant found within the amyloid precursor protein (APP) gene conferring protection against Alzheimer's disease (AD). Thereafter, different studies have discovered that the carriers of the APP A673T variant show reduced levels of amyloid beta (Aβ) in the plasma and better cognitive performance at high age. Here, we analyzed cerebrospinal fluid (CSF) and plasma of APP A673T carriers and control individuals using a mass spectrometry-based proteomics approach to identify differentially regulated targets in an unbiased manner. Furthermore, the APP A673T variant was introduced into 2D and 3D neuronal cell culture models together with the pathogenic APP Swedish and London mutations. Consequently, we now report for the first time the protective effects of the APP A673T variant against AD-related alterations in the CSF, plasma, and brain biopsy samples from the frontal cortex. The CSF levels of soluble APPβ (sAPPβ) and Aβ42 were significantly decreased on average 9–26% among three APP A673T carriers as compared to three well-matched controls not carrying the protective variant. Consistent with these CSF findings, immunohistochemical assessment of cortical biopsy samples from the same APP A673T carriers did not reveal Aβ, phospho-tau, or p62 pathologies. We identified differentially regulated targets involved in protein phosphorylation, inflammation, and mitochondrial function in the CSF and plasma samples of APP A673T carriers. Some of the identified targets showed inverse levels in AD brain tissue with respect to increased AD-associated neurofibrillary pathology. In 2D and 3D neuronal cell culture models expressing APP with the Swedish and London mutations, the introduction of the APP A673T variant resulted in lower sAPPβ levels. Concomitantly, the levels of sAPPα were increased, while decreased levels of CTFβ and Aβ42 were detected in some of these models. Our findings emphasize the important role of APP-derived peptides in the pathogenesis of AD and demonstrate the effectiveness of the protective APP A673T variant to shift APP processing towards the non-amyloidogenic pathway in vitro even in the presence of two pathogenic mutations.

A randomized, open-label clinical trial in mild cognitive impairment with EGb 761 examining blood markers of inflammation and oxidative stress

Although beta-amyloid (Aβ) and phosphorylated tau remain the preferred targets for disease-modifying treatments (DMT) against Alzheimer’s disease (AD), part of the pathophysiological mechanisms of cognitive impairment are related to neuroinflammation and oxidative stress. In mild cognitive impairment (MCI), a prodromal stage of AD and other neurodegenerative conditions, the joint appearance of inflammation, oxidative stress, and metabolic alterations are the common pathways of neurotoxicity and neurodegeneration. The standardized extract of Ginkgo biloba EGb 761 interferes with the pathogenic mechanisms involved in both the development of cognitive impairment due to AD and that of vascular origin. The primary objective of this study is to compare changes in the levels of blood markers of inflammation and oxidative stress after treatment with EGb 761 in a cohort of 100 patients with MCI. In addition, we aim to assess changes in these blood markers during an additional 12-month extension phase in which patients in the control group will also receive EGb 761 and patients in the active group will extend their treatment duration. Secondary objectives include comparing changes in neuropsychiatric and cognitive test scores between the baseline (v0) and 12-month visits (v2). This study is a Phase IV, single-center, randomized, open-label, parallel-group clinical trial consisting of the 12-month follow-up of a cohort of participants with MCI [Global Deterioration Scale (GDS) = 3] and an extension with an additional 12-month follow-up. During the first 12 months, participants will be randomized into two arms: in one arm, patients will receive 1 daily tablet of EGb 761 240 mg orally (study group, n = 50), while in the other arm, patients will not receive EGb 761 and will undergo the same assessments as the treated group (control group, n = 50). After the first 12 months of the study, patients in the EGb 761-treated group will continue treatment, and patients in the control group will be offered one EGb 761 240 mg tablet per day orally. All participants will be monitored for an additional 12 months. A battery of blood markers of inflammation and oxidative stress will be quantified at v0, v1, v2, v3, and v4. The Olink Proteomics panel of inflammation markers (https://www.olink.com/products/inflammation/) will be used to evaluate 92 proteins associated with inflammatory diseases and related biological processes. The second panel measures 92 proteins involved in neurological processes. At v0, v2, and v4, neuropsychological and neurological evaluations will be conducted in addition to vital signs and anthropometric studies using a body composition monitor with bioimpedance technology (Tanita). Sixty percent of the 100 MCI patients recruited were women. The mean age was 73.1 years, and the mean time between symptom onset and MCI diagnosis was 2.9 years. The mean Mini-Mental State Examination (MMSE) score was 26.7. Depressive and anxiety disorders, as well as vascular risk factors, were the most frequent comorbidities among the cohort. The study is still ongoing, and results for the first year of treatment (v0, v1, v2) are expected by 2023. Individuals with MCI have an elevated risk of developing dementia. EGb 761 is used worldwide for the symptomatic treatment of cognitive disorders due to its neuroprotective effects. In experimental models and clinical observational studies, EGb 761 has shown strong antioxidant and anti-inflammatory activity. As a result, this study has been proposed to evaluate the antioxidant and anti-inflammatory effects on plasma markers and their potential clinical correlation with the progression of cognitive decline in patients with MCI.Trial registration: Registro Español de estudios clínicos (REec) number 2020-003776-41, ClinicalTrials.gov Identifier: NCT05594355.