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Alzheimer's disease is a neurodegenerative disease induced by multiple interconnected mechanisms. Peptide drug candidates with multi-modal efficacy generated from fusion strategy are suitable for addressing multi-facet pathology. However, clinical translation of peptide drugs is greatly hampered by their low permeability into brain. Herein, a hybrid peptide HNSS is generated by merging two therapeutic peptides (SS31 and S-14 G Humanin (HNG)), using a different approach from the classical shuttle-therapeutic peptide conjugate design. HNSS demonstrated increased bio-permeability, with a 2-fold improvement in brain distribution over HNG, thanks to its structure mimicking the design of signal peptide-derived cell-penetrating peptides. HNSS efficiently alleviated mitochondrial dysfunction through the combined effects of mitochondrial targeting, ROS scavenging and p-STAT3 activation. Meanwhile, HNSS with increased Aß affinity greatly inhibited Aß oligomerization/fibrillation, and interrupted Aß interaction with neuron/microglia by reducing neuronal mitochondrial Aß deposition and promoting microglial phagocytosis of Aß. In 3× Tg-AD transgenic mice, HNSS treatment efficiently inhibited brain neuron loss and improved the cognitive performance. This work validates the rational fusion design-based strategy for bio-permeability improvement and efficacy amplification, providing a paradigm for developing therapeutic peptide candidates against neurodegenerative disease.

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Amyloid-ß (Aß) species (Aß fibrils and Aß plaques), as one of the typical pathological markers of Alzheimer's disease (AD), plays a crucial role in AD diagnosis. Currently, some near-infrared I (NIR I) Aß probes have been reported in AD diagnosis. However, they still face challenges such as strong background interference and the lack of effective probe design. In this study, we propose molecular design strategy that incorporates CN group and amphiphilic modulation to synthesize a series of amphiphilic NIR I Aß probes, surpassing the commercial probe ThT and ThS. Theoretical calculations indicate that these probes exhibit stronger interaction with amino acid residues in the cavities of Aß. Notably, the probes containing CN group display the ability of binding two distinct sites of Aß, which dramatically enhanced the affinity to Aß species. Furthermore, these probes exhibit minimal fluorescence in aqueous solution and offer ultra-high signal-to-noise ratio (SNR) for in vitro labeling, even in wash-free samples. Finally, the optimal probe DM-V2CN-PYC3 was utilized for in vivo imaging of AD mice, demonstrating its rapid penetration through the blood-brain barrier and labelling to Aß species. Moreover, it enabled long-term monitoring for a duration of 120 min. These results highlight the enhanced affinity and superior performance of the designed NIR I Aß probe for AD diagnosis. The molecular design strategy of CN and amphiphilic modulation presents a promising avenue for the development Aß probes with low background in vivo/in vitro imaging for Aß species.

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BACKGROUND: Although diagnostic markers in cerebrospinal fluid (CSF) have become a rapidly growing research field, they have not as yet been investigated in relation to capacities that are of interest to geriatric psychiatry and neuropsychology, such as financial capacity. The aim of this study was to assess whether CSF biomarkers can predict financial capacity in patients with a diagnosis of major neurocognitive disorder due to Alzheimer's disease (AD). METHODS: Participants were examined with a number of neuropsychological tests, with an emphasis on the Mini-Mental State Examination (MMSE), the Geriatric Depression Scale (GDS-15), and the Legal Capacity for Property Law Transactions Assessment Scale (LCPLTAS) and CSF tests. RESULTS: Amyloid ß peptide 1-42 (Aß42), total tau, and phosphorylated tau were not found to predict financial capacity performance in AD, but MMSE shows a strong positive correlation with LCPLTAS. CONCLUSIONS: These preliminary findings indicate that complex cognitive functions, such as financial capacity, may not be directly linked to CSF concentrations of the abovementioned biomarkers. Further studies with larger numbers of patients will be required to assess the reproducibility of these findings and to determine whether this approach can assist not only in diagnosis but also in neuropsychological assessment.

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Amyloid-beta peptide oligomers (AßO) have been considered "primum movens" for a cascade of events that ultimately cause selective neuronal death in Alzheimer's disease (AD). However, initial events triggered by AßO have not been clearly defined. Synaptic (Syn) N-methyl-d-aspartate receptors (NMDAR) are known to activate cAMP response element-binding protein (CREB), a transcriptional factor involved in gene expression related to cell survival, memory formation and synaptic plasticity, whereas activation of extrasynaptic (ESyn) NMDARs was linked to excitotoxic events. In AD brain, CREB phosphorylation/activation was shown to be altered, along with dyshomeostasis of intracellular Ca2+ (Ca2+ i). Thus, in this work, we analyze acute/early and long-term AßO-mediated changes in CREB activation involving Syn or ESyn NMDARs in mature rat cortical neurons. Our findings show that acute AßO exposure produce early increase in phosphorylated CREB, reflecting CREB activity, in a process occurring through Syn NMDAR-mediated Ca2+ influx. Data also demonstrate that AßO long-term (24 h) exposure compromises synaptic function related to Ca2+-dependent CREB phosphorylation/activation and nuclear CREB levels and related target genes, namely Bdnf, Gadd45γ, and Btg2. Data suggest a dual effect of AßO following early or prolonged exposure in mature cortical neurons through the activation of the CREB signaling pathway, linked to the activation of Syn NMDARs.

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Positive effects of new anti-amyloid-ß (Aß) monoclonal antibodies in Alzheimer's disease (AD) have been attributed to brain amyloid reduction. However, most anti-Aß antibodies also increase the CSF levels of the 42-amino acid isoform (Aß42). We evaluated the associations of changes in CSF Aß42 and brain Aß-PET with cognitive and clinical end points in randomized trials of anti-Aß drugs that lowered (ß- and γ-secretase inhibitors) or increased CSF Aß42 levels (anti-Aß monoclonal antibodies) to test the hypothesis that post-treatment increases in CSF Aß42 levels are independently associated with cognitive and clinical outcomes. From long-term (≥12 months) randomized placebo-controlled clinical trials of anti-Aß drugs published until November 2023, we calculated the post-treatment versus baseline difference in ADAS-Cog (cognitive subscale of the Alzheimer's Disease Assessment Scale) and CDR-SB (Clinical Dementia Rate-Sum of Boxes) and z-standardized changes in CSF Aß42 and Aß-PET Centiloids (CL). We estimated the effect size [regression coefficients (RCs) and confidence intervals (CIs)] and the heterogeneity (I2) of the associations between AD biomarkers and cognitive and clinical end points using random-effects meta-regression models. We included 25 966 subjects with AD from 24 trials. In random-effects analysis, increases in CSF Aß42 were associated with slower decline in ADAS-Cog (RC: -0.55; 95% CI: -0.89, -0.21, P = 0.003, I2 = 61.4%) and CDR-SB (RC: -0.16; 95% CI: -0.26, -0.06, P = 0.002, I2 = 34.5%). Similarly, decreases in Aß-PET were associated with slower decline in ADAS-Cog (RC: 0.69; 95% CI: 0.48, 0.89, P < 0.001, I2 = 0%) and CDR-SB (RC: 0.26; 95% CI: 0.18, 0.33, P < 0.001, I2 = 0%). Sensitivity analyses yielded similar results. Higher CSF Aß42 levels after exposure to anti-Aß drugs are independently associated with slowing cognitive impairment and clinical decline. Increases in Aß42 may represent a mechanism of potential benefit of anti-Aß monoclonal antibodies in AD.

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INTRODUCTION: Dementia often involves comorbid Alzheimer's and vascular pathology, but their combined impact warrants additional study. METHODS: We analyzed the Systolic Blood Pressure Intervention Trial and categorized white matter hyperintensity (WMH) volume into highest versus lowest/mid tertile and the amyloid beta (Aß)42/40 ratio into lowest versus mid/highest ratio tertile. Using these binary variables, we created four exposure categories: (1) combined low risk, (2) Aß risk, (3) WMH risk, and (4) combined high risk. RESULTS: In the cohort of 467 participants (mean age 69.7 ± 7.1, 41.8% female, 31.9% nonwhite or Hispanic) during 4.8 years of follow-up and across the four exposure categories the rates of cognitive impairment were 5.3%, 7.8%, 11.8%, and 22.6%. Compared to the combined low-risk category, the adjusted hazard ratio for cognitive impairment was 4.12 (95% confidence interval, 1.71 to 9.94) in the combined high-risk category. DISCUSSION: This study emphasizes the potential impact of therapeutic approaches to dementia prevention that target both vascular and amyloid pathology. HIGHLIGHTS: White matter hyperintensity (WMH) and plasma amyloid (Aß42/40) are additive risk factors for the development of cognitive impairment in the SPRINT MIND trial. Individuals in the high-risk categories of both WMH and Aß42/40 had a near fivefold increase in risk of cognitive impairment during 4.8 years of follow-up on average. These findings suggest that treatment strategies targeting both vascular health and amyloid burden warrant further research.

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IMPORTANCE: Alzheimer's disease (AD) is the most common cause of dementia in the elderly with the incidence rising exponentially after the age of 65 years. Unfortunately, effective treatments are extremely limited and definite diagnosis can only be made at autopsy. This is in part due to our limited understanding of the complex pathophysiology, including the various genetic, environmental, and metabolic contributing factors. In an effort to better understand this complex disease, researchers have employed nonhuman primates as translational models. CASE PRESENTATION: This report aims to describe the AD-like neuropathology in the brain of a 37-year-old female baboon (Papio hamadryas), which at the time of her death made her the oldest hamadryas baboon at any member institution of the Association of Zoos and Aquariums. A diagnostic necropsy was performed, and the brain was evaluated for neurodegenerative disease. Frequent amyloid-ß deposits were identified, consistent with what has been described in other geriatric nonhuman primates. Phospho-tau pathology, including neurofibrillary tangles, a feature not well-described in other primate models, was also abundant. CONCLUSIONS AND RELEVANCE: Our results suggest that more detailed, prospective, longitudinal studies are warranted utilizing this particular species to see if they represent a viable model for human brain aging.

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Previous studies have suggested that N6-methyladenosine (mA) modification of RNA affects fundamental aspects of RNA metabolism, and mA dysregulation is implicated in various human diseases, including Alzheimer's disease (AD). This study is designed to explore the role and mechanism of methyltransferase-like 14 (METTL14) in the pathogenesis of AD. SK-N-SH cells were treated with Aß1-42 to establish an in vitro model of AD. Cerebellin 4 (CBLN4) and METTL14 expression levels were detected by real-time quantitative polymerase chain reaction (RT-qPCR). Cell viability and apoptosis were analyzed using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and flow cytometry assay. B-cell lymphoma-2 (Bcl-2), Bcl-2 related X protein (Bax), C-caspase-3, total-caspase-3, C/EBP homologous protein (CHOP), and glucose-related protein 78 (GRP78) protein levels were determined using Western blot. Interleukin-1ß (IL-1ß) and tumor necrosis factor α (TNF-α) levels were analyzed using ELISA. Reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD) products were examined using special assay kits. Interaction between CBLN4 and METTL14 was verified using methylated RNA immunoprecipitation (MeRIP) and dual-luciferase reporter assays. CBLN4 and METTL14 expression was decreased in Aß1-42-treated SK-N-SH cells. Upregulation of CBLN4 relieved Aß1-42-induced SK-N-SH cell apoptosis, inflammation, oxidative stress, and endoplasmic reticulum (ER) stress in vitro. At the molecular level, METTL14 could improve the stability and expression of CBLN4 mRNA via m6A methylation. Our findings indicated that m6A methylase METTL14-mediated upregulation of CBLN4 mRNA stability could repress Aß1-42-triggered SK-N-SH cell injury, providing a promising therapeutic target for AD treatment.

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BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder primarily affecting the elderly, characterized by severe cognitive impairment and memory loss. Emerging evidence suggests that neuroinflammation plays a significant role in AD pathogenesis, with cytokines like interleukin-6 (IL-6) and C-X-C motif chemokine ligand 8 (CXCL8) contributing to the disease progression. METHODS: We utilized GEO datasets to identify IL-6 and CXCL8 as pivotal inflammatory markers in AD. In vitro experiments were conducted using SK-N-BE(2)-M17 and THP-1 cell lines treated with IL-6 and CXCL8 to model AD. Additionally, in vivo tests on Amyloid Precursor Protein/Presenilin 1 (APP/PS1) AD mouse models were performed to assess the impact of these cytokines on cognitive functions and brain pathology. RESULTS: The results indicated a significant decrease in cell viability, increased apoptosis, and elevated inflammatory factor secretion following IL-6 and CXCL8 treatment in vitro. In vivo, AD mouse models treated with these cytokines exhibited exacerbated emotional distress, decreased social interaction, impaired cognitive functions, and increased amyloid protein deposition in neural tissues. CONCLUSIONS: The study highlights the detrimental effects of IL-6 and CXCL8 on neuronal health and cognitive functions in AD. These findings suggest that targeting these cytokines could offer potential therapeutic interventions for improving patient outcomes in Alzheimer's disease.

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OBJECTIVES: Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment. This situation imposes a great burden on individuals, both economically and socially. Today, an effective method for treating the disease and protective approach to tau accumulation has not been developed yet. Studies have been conducted on the effects of hesperidin and naringin flavonoids found in citrus fruits on many diseases. METHODS: In this review, the pathophysiology of AD is defined, and the effects of hesperidin and naringin on these factors are summarized. RESULTS: Studies have shown that both components may potentially affect AD due to their antioxidative and anti-inflammatory properties. Based on these effects of the components, it has been shown that they may have ameliorative effects on Aß, α-synuclein aggregation, tau pathology, and cognitive functions in the pathophysiology of AD. DISCUSSION: There are studies suggesting that hesperidin and naringin may be effective in the prevention/treatment of AD. When these studies are examined, it is seen that more studies should be conducted on the subject.

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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by complex pathogenesis mechanisms. Among these, ß-amyloid plaques and hyperphosphorylated Tau protein tangles have been identified as significant contributors to neuronal damage. This study investigates thonningianin A (TA) from Penthorum chinense Pursh (PCP) as a potential inhibitor targeting these pivotal proteins in AD progression. The inhibitory potential of PCP and TA on Aß fibrillization was initially investigated. Subsequently, ultra-high performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry and biolayer interferometry were employed to determine TA's affinity for both Aß and Tau. The inhibitory effects of TA on the levels and cytotoxicity of AD-related proteins were then assessed. In 3xTg-AD mice, the therapeutic potential of TA was evaluated. Additionally, the molecular interactions between TA and either Aß or Tau were explored using molecular docking. We found that PCP-total ethanol extract and TA significantly inhibited Aß fibrillization. Additionally, TA demonstrated strong affinity to Aß and Tau, reduced levels of amyloid precursor protein and Tau, and alleviated mitochondrial distress in PC-12 cells. In 3xTg-AD mice, TA improved cognition, reduced Aß and Tau pathology, and strengthened neurons. Moreover, molecular analyses revealed efficient binding of TA to Aß and Tau. In conclusion, TA, derived from PCP, shows significant neuroprotection against AD proteins, highlighting its potential as an anti-AD drug candidate.

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ETHNOPHARMACOLOGICAL RELEVANCE: Research suggests that traditional Chinese medicine (TCM) holds promise in offering innovative approaches to tackle neurodegenerative disorders. In our endeavor, we conducted a comprehensive bibliometric analysis to delve into the landscape of TCM research within the realm of neurodegenerative diseases, aiming to uncover the present scenario, breadth, and trends in this field. This analysis presents potentially valuable insights for the clinical application of traditional Chinese medicine and provides compelling evidence supporting its efficacy in the treatment of neurodegenerative conditions. AIM OF THE STUDY: The incidence of neurodegenerative diseases is on the rise, yet effective treatments are still lacking. Research indicates that TCM could offer novel perspectives for addressing neurodegenerative conditions. Nonetheless, the literature on this topic is intricate and multifaceted, with existing reviews offering only limited coverage. To gain a thorough understanding of TCM research in neurodegenerative diseases, we undertook a bibliometric analysis to explore the current status, scope, and trends in this area. MATERIALS AND METHODS: A literature search was carried out on April 1, 2024, utilizing the Web of Science Core Collection (WoSCC). Visualization and quantitative analyses were then performed with the assistance of CiteSpace, VOSviewer, and R software. RESULTS: A total of 6856 articles were retrieved in the search. Research on TCM for neurodegenerative diseases commenced in 1989 and has exhibited a notable overall growth since then. Main research contributors include East Asian countries like China, as well as the United States. Through our analysis, we identified 15 highly productive authors, 10 top-tier journals, 13 citation clusters, 11 influential articles, and observed a progression in keyword evolution across 4 distinct categories. In 2020, there was a significant upsurge in the knowledge base, collaboration efforts, and publication output within the field. This field is interdisciplinary: network pharmacology emerges as the cutting-edge paradigm in TCM research, while Alzheimer's disease remains a prominent focus among neurodegenerative conditions due to its evolving etiology. A burst detection analysis unveils that in 2024, the focal points of research convergence between TCM and neurodegenerative diseases lie in two key biological processes or mechanisms: autophagy and microbiota. CONCLUSIONS: For the first time, this study quantitatively and visually captures the evolution of TCM in addressing neurodegenerative diseases, showcasing a notable acceleration in recent years. Our findings underscore the pivotal role of interdisciplinary collaboration and the necessity for increased global partnerships. Network pharmacology, leveraging the advancements of the big data era, embraces a holistic and systematic approach as a novel paradigm in exploring traditional Chinese medicine and unraveling their fundamental mechanisms. Three ethnomedical plants-Tianma, Renshen, and Wuweizi-demonstrate the promise of their bioactive compounds in treating neurodegenerative disorders, bolstered by their extensive historical usage for such ailments. Moreover, our intricate analysis of the evolutionary trajectories of key themes such as targets and biomarkers substantially enriches our comprehension of the underlying mechanisms involved.

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Imidacloprid (IMI), the most widely used worldwide neonicotinoid biocide, produces cognitive disorders after repeated and single treatment. However, little was studied about the possible mechanisms that produce this effect. Cholinergic neurotransmission regulates cognitive function. Most cholinergic neuronal bodies are present in the basal forebrain (BF), regulating memory and learning process, and their dysfunction or loss produces cognition decline. BF SN56 cholinergic wild-type or acetylcholinesterase (AChE), ß-amyloid-precursor-protein (ßAPP), Tau, glycogen-synthase-kinase-3-beta (GSK3ß), beta-site-amyloid-precursor-protein-cleaving enzyme 1 (BACE1), and/or nuclear-factor-erythroid-2-related-factor-2 (NRF2) silenced cells were treated for 1 and 14 days with IMI (1 µM-800 µM) with or without recombinant heat-shock-protein-70 (rHSP70), recombinant proteasome 20S (rP20S) and with or without N-acetyl-cysteine (NAC) to determine the possible mechanisms that mediate this effect. IMI treatment for 1 and 14 days altered cholinergic transmission through AChE inhibition, and triggered cell death partially through oxidative stress generation, AChE-S overexpression, HSP70 downregulation, P20S inhibition, and Aß and Tau peptides accumulation. IMI produced oxidative stress through reactive oxygen species production and antioxidant NRF2 pathway downregulation, and induced Aß and Tau accumulation through BACE1, GSK3ß, HSP70, and P20S dysfunction. These results may assist in determining the mechanisms that produce cognitive dysfunction observed following IMI exposure and provide new therapeutic tools.

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Alzheimer's disease (AD, also known as dementia) has become a serious global health problem along with population aging, and neuroinflammation is the underlying cause of cognitive impairment in the brain. Nowadays, the development of multitarget anti-AD drugs is considered to be one effective approach. Imidazolylacetophenone oxime ethers or esters (IOEs) were multifunctional agents with neuroinflammation inhibition, metal chelation, antioxidant and neuroprotection properties against Alzheimer's disease. In this study, IOEs derivatives 1-8 were obtained by structural modifications of the oxime and imidazole groups, and the SARs showed that (Z)-oxime ether (derivative 2) had stronger anti-neuroinflammatory and neuroprotective ability than (E)-congener. Then, IOEs derivatives 9-30 were synthesized based on target-directed ligands and activity-based groups hybridization strategy. In vitro anti-AD activity screening revealed that some derivatives exhibited potentially multifunctional effects, among which derivative 28 exhibited the strongest inhibitory activity on NO production with EC50 value of 0.49 µM, and had neuroprotective effects on 6-OHDA-induced cell damage and RSL3-induced ferroptosis. The anti-neuroinflammatory mechanism showed that 28 could inhibit the release of pro-inflammatory factors PGE2 and TNF-α, down-regulate the expression of iNOS and COX-2 proteins, and promote the polarization of BV-2 cells from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype. In addition, 28 can dose-dependently inhibit acetylcholinesterase (AChE) and Aß42 aggregation. Moreover, the selected nuclide [18F]-labeled 28 was synthesized to explore its biodistribution by micro-PET/CT, of which 28 can penetrate the blood-brain barrier (BBB). These results shed light on the potential of 28 as a new multifunctional candidate for AD treatment.

Asunto(s)

Acetofenonas , Enfermedad de Alzheimer , Diseño de Fármacos , Imidazoles , Fármacos Neuroprotectores , Oximas , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Oximas/química , Oximas/farmacología , Oximas/síntesis química , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/síntesis química , Animales , Relación Estructura-Actividad , Imidazoles/farmacología , Imidazoles/química , Imidazoles/síntesis química , Acetofenonas/química , Acetofenonas/farmacología , Acetofenonas/síntesis química , Estructura Molecular , Humanos , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Acetilcolinesterasa/metabolismo , Relación Dosis-Respuesta a Droga , Ratas , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química

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Low body mass index is closely related to a high risk of Alzheimer's disease (AD) and related biomarkers including amyloid-ß (Aß) deposition. However, the association between sarcopenia and Aß-confirmed AD remains controversial. Therefore, we investigated the relationship between sarcopenia and the AD continuum. We explored sarcopenia's association with clinical implications of participants on the AD continuum. We prospectively enrolled 142 participants on the AD continuum (19 with preclinical AD, 96 with mild cognitive impairment due to AD, and 28 with AD dementia) and 58 Aß-negative cognitively unimpaired participants. Sarcopenia, assessed using dual-energy X-ray absorptiometry and hand grip measurements, was considered a predictor. AD continuum, defined by Aß deposition on positron emission tomography served as an outcome. Clinical severity in participants on the AD continuum assessed using hippocampal volume, Mini-Mental State Examination (MMSE), Seoul Verbal Learning Test (SVLT), and Clinical Dementia Rating Scale Sum of Boxes Scores (CDR-SOB) were also considered an outcome. Sarcopenia (odds ratio = 4.99, p = 0.004) was associated independently with the AD continuum after controlling for potential confounders. Moreover, sarcopenia was associated with poor downstream imaging markers (decreased hippocampal volume, ß = - 0.206, p = 0.020) and clinical outcomes (low MMSE, ß = - 1.364, p = 0.025; low SVLT, ß = - 1.077, p = 0.025; and high CDR-SOB scores, ß = 0.783, p = 0.022) in participants on the AD continuum. Sarcopenia was associated with the AD continuum and poor clinical outcome in individuals with AD continuum. Therefore, our results provide evidence for future studies to confirm whether proper management of sarcopenia can effective strategies are required for sarcopenia management to prevent the AD continuum and its clinical implications.

Asunto(s)

Enfermedad de Alzheimer , Disfunción Cognitiva , Sarcopenia , Humanos , Sarcopenia/diagnóstico por imagen , Sarcopenia/etiología , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/diagnóstico por imagen , Femenino , Masculino , Anciano , Tomografía de Emisión de Positrones , Anciano de 80 o más Años , Péptidos beta-Amiloides/metabolismo , Fuerza de la Mano , Estudios Prospectivos , Biomarcadores , Absorciometría de Fotón , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Hipocampo/metabolismo , Pruebas de Estado Mental y Demencia , Índice de Masa Corporal

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Recent advances in clinical passive immunotherapy have provided compelling evidence that eliminating amyloid-ß (Aß) slows cognitive decline in Alzheimer's disease (AD). However, the modest benefits and side effects observed in clinical trials indicate that current immunotherapy therapy is not a panacea, highlighting the need for a deeper understanding of AD mechanisms and the significance of early intervention through optimized immunotherapy or immunoprevention. This review focuses on the centrality of Aß pathology in AD and summarizes recent clinical progress in passive and active immunotherapies targeting Aß, discussing their lessons and failures to inform future anti-Aß biotherapeutics design. Various delivery strategies to optimize Aß-targeting immunotherapies are outlined, highlighting their benefits and drawbacks in overcoming challenges such as poor stability and limited tissue accessibility of anti-Aß biotherapeutics. Additionally, the perspectives and challenges of immunotherapy and immunoprevention targeting Aß are concluded in the end, aiming to guide the development of next-generation anti-Aß immunotherapeutic agents towards improved efficacy and safety.

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Background: Plasma biomarker has the potential to be the reliable and propagable approach in the early stage diagnosis of Alzheimer's disease (AD). However, conventional methods appear powerless in the detection of these biomarkers at low concentrations in plasma. Here, we determined plasma biomarker concentrations of patients across the AD spectrum by an improved digital enzyme-linked immunosorbent assay (ELISA) technique. Confirms the predictive and diagnostic value of this method for AD patients and study the relationships between these biomarkers and cognitive status. Methods: Plasma concentrations of amyloid-beta 40 (Aß40), amyloid-beta 42 (Aß42) and plasma phosphorylated tau at threonine 181 (p-tau181) were determined in 43 AD patients, 33 mild cognitive impairment (MCI) patients and 40 normal cognition (NC) subjects as healthy controls using the improved digital ELISA technique. In addition, all subjects were required to receive neuropsychological assessments. Results: Plasma p-tau181 level showed certain discrepancies between NC and MCI (p < 0.05), AD (p < 0.01) groups. The level of plasma Aß42 (p < 0.05) and Aß40 (p < 0.01) was significantly different between AD and NC group. The p-tau181 level was able to distinguish AD (AUC = 0.8768) and MCI (AUC = 0.7932) from NC with higher accuracy than Aß42/Aß40 ratio (AUC = 0.8343, AUC = 0.6569). Both p-tau181 (CDR: r = 0.388 p < 0.001; MMSE: r = -0.394 p < 0.001) and Aß42/Aß40 ratio (CDR: r = -0.413 p < 0.001; MMSE: r = 0.358 p < 0.001) showed stronger positive correlation with clinical dementia rating (CDR) and mini mental state examination (MMSE) scores than Aß42 (CDR: r = -0.280 p = 0.003; MMSE: r = 0.266 p = 0.005) or Aß40 (CDR: r = 0.373 p < 0.001; MMSE: r = -0.288 p = 0.002) alone. Conclusion: Plasma p-tau181 level and Aß42/Aß40 ratio showed promising values in diagnosis of AD and MCI. Our results indicate that this improved digital ELISA diagnosis approach can facilitate early recognition and management of AD and pre-AD patients.

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Wild fruits, particularly the underutilized sloe (Prunus spinosa), are gaining interest as natural antioxidants, with residues from liqueur production being a source of bioactive compounds. This study proposes a sustainable approach for valorizing sloe residues, seeds and skins, by employing an innovative green extraction method. HPLC-ESI-QTOF and spectrophotometric techniques were used to explore the phenolic profile, highlighting the predominance of quercetin, 2,3-dihydroxybenzoic and ferulic acids (9.7-57 µg·g-1). In addition, the presence of Cu, Zn and Ca was confirmed by atomic absorption spectroscopy. Simultaneously, their neuroprotective potential against Alzheimer's disease (AD) was studied by exploring the inhibition of beta-amyloid aggregation and oxidative stress cytoprotection in SH-SY5Y cell line, standing out 1 µg·g-1 and 10 µg·g-1 extracts of sloe skin. Phenolic composition was correlated with bioactivities by means of multivariate analysis. These results contributed to highlight the potential of this bio-residue as a neuroprotective agent against AD in pharmaceutical and nutraceutical industries.

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The complex nature of Alzheimer's disease (AD) etiopathology is among the principal hurdles to developing effective anti-Alzheimer agents. Tau pathology and Amyloid-ß (Aß) accumulation are hallmarks and validated therapeutic strategies of AD. GSK-3ß is a serine/threonine kinase involved in tau phosphorylation. Its excessive activity also contributes to the production of Aß plaques, making GSK-3ß an attractive AD target. Taking this into account, In this article, we outline the design, synthesis, and biological validation of a focused library of 1,2,3,4-tetrahydropyrimidine based derivatives as inhibitors of GSK-3ß, tau phosphorylation, and Aß accumulation. The inhibitory activity of forty nine synthetic compounds was tested against GSK-3ß and other AD-relevant kinases. The kinetic experiments revealed the mode of GSK-3ß inhibition by the most potent compound 44. The in- vitro drug metabolism and pharmacokinetic studies were thereafter performed. The anti-aggregation activity of the most potent GSK-3ß inhibitor was tested using AD transgenic Caenorhabditis elegans (C. elegans) strain CL2006 for quantification of Aß plaques and BR5706 C. elegans strain for tau pathology evaluation. We then evaluated the blood-brain barrier permeability and got promising results. Therefore, we present compound 44 as a potential ATP-competitive GSK-3ß inhibitor with good metabolism and pharmacokinetic profile, anti-aggregation properties for amyloid beta protein, and reduction in tau-phosphorylation levels. We recommend more investigation into compound 44-based small molecules as possible targets for AD disease-modifying treatments.

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Atorvastatin an HMGCR inhibitor may play a role in enhancing spatial and long-term memory and combating anxious behavior deficits induced by Aß1-42. Behavioral deficit studies, immunoblotting for the antioxidant/apoptotic protein expression, flow cytometry (FACS) for mitochondrial ROS, membrane potential (▲ψm), and histopathological alterations were performed against Aß1-42 toxicity. Aß1-42 was infused directly into the brain through i.c.v for the establishment of the AD model. Atorvastatin (ATOR) was administered orally and was used to treat AD in adult male Wistar rats aged between 200 and 250 g. We confirmed that ATOR administration significantly attenuates the Aß1-42-induced cognitive decline targeted mitochondrial-mediated age-dependent disease progression. Nrf2 stabilizes to interact SOD2 antioxidant enzyme, allowing transcriptional activity by the steep increase in ▲ψm and a reduction in ROS by activating mitochondrial superoxide scavenger and Nrf2-dependent pathway. These findings confirmed that ATOR has the potential efficacy to modulate the interference in cognitive decline induced by Aß1-42.