ACS Applied Materials & Interfaces
·
2023
·
IF 9.5
Qin-ying Li,Xu Yu,Xi Li,Li-na Bao,Yu Zhang,Min-Jie Xie,Ming Jiang,Ya Qian Wang,Kun Huang,Li Xu
The redox-active metal ions, especially Cu2+, are highly correlated to Alzheimer’s disease (AD) by causing metal ion-mediated oxidative stress and toxic metal-bound β-amyloid (Aβ) aggregates. Numerous pieces of evidence have revealed that the regulation of metal homeostasis could be an effective therapeutic strategy for AD. Herein, in virtue of the interaction of both amino-containing silane and ethylenediaminetetraacetic acid disodium salt for Cu2+, the silicon–carbon dots (SiCDs) are deliberately prepared using these two raw materials as the cocarbon source; meanwhile, to realize the local enrichment of SiCDs and further maximize the chelating ability to Cu2+, the SiCDs are feasibly loaded to the biocompatible mesoporous silica nanoparticles (mSiO2) with the interaction between residual silane groups on SiCDs and silanol groups of mSiO2. Thus-obtained nanocomposites (i.e., mSiO2@SiCDs) could serve as an efficient Cu2+ chelator with satisfactory metal selectivity and further modulate the enzymic activity of free Cu2+ and the Aβ42–Cu2+ complex to alleviate the pathological oxidative stress with an anti-inflammatory effect. Besides, mSiO2@SiCDs show an inspiring inhibitory effect on Cu2+-mediated Aβ aggregation and further protect the neural cells against the toxic Aβ42–Cu2+ complex. Moreover, the transgenic Caenorhabditis elegans CL2120 assay demonstrates the protective efficacy of mSiO2@SiCDs on Cu2+-mediated Aβ toxicity in vivo, indicating its potential for AD treatment.
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PubMed
高影响因子
Bioengineering & Translational Medicine
·
2022
·Vol. 7
·期 3
·e10395
·
IF 10.684
Ruiyi Zhou,Lihong Zhu,Zhaohao Zeng,Rixin Luo,Jiawei Zhang,Rui Guo,Lei Zhang,Qunying Zhang,Wei Bi
Alzheimer's disease (AD) is an aging-related neurodegenerative disease. The main pathological features of AD are β-amyloid protein (Aβ) deposition and tau protein hyperphosphorylation. Currently, there are no effective drugs for the etiological treatment of AD. Rifampicin (RIF) is a semi-synthetic broad-spectrum antibiotic with anti-β-amyloid deposition, anti-inflammatory, anti-apoptosis, and neuroprotective effects, but its application in AD treatment has been limited for its strong hydrophobicity, high toxicity, short half-life, low bioavailability, and blood–brain barrier hindrance. We designed a novel brain-targeted and MRI-characteristic nanomedicine via loading rabies virus protein 29 (RVG29), rifampicin, and Gd on poly ( l -lactide) nanoparticles (RIF@PLA-PEG-Gd/Mal-RVG29). The cytotoxicity assay demonstrated that RIF@PLA-PEG-Gd/Mal-RVG29 had favorable biocompatibility and security. Fluorescence imaging in vivo showed that PLA-PEG-Gd/Mal-RVG29 could deliver rifampicin into the brain by enhancing cellular uptake and brain targeting performance, leading to improvement of the bioavailability of rifampicin. In in vivo study, RIF@PLA-PEG-Gd/Mal-RVG29 improved the spatial learning and memory capability of APP/PS1 mice in the Morris water maze, as compared to rifampicin. Immunofluorescence, TEM, immunoblotting, and H&E staining revealed that RIF@PLA-PEG-Gd/Mal-RVG29 reduced Aβ deposition in hippocampal and cortex of APP/PS1 mice, improved the damage of synaptic ultrastructure, increased the expression level of PSD95 and SYP, as well as reduced the necrosis of neurons. These findings suggest that RIF@PLA-PEG-Gd/Mal-RVG29 may be an effective strategy for the treatment of AD.
研究领域:
神经科学
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药学
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纳米技术
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药物递送系统
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PubMed
高影响因子
PSYCHOPHARMACOLOGY
·
2021
·Vol. 239
·期 1
·215-227
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IF 4.53
Wang Chen,Zheng Dongpeng,Weng Fanglin,Jin Yongzeng,He Ling
Rationale Energy metabolism disorder is a widespread feature that exists in the early clinical stages of Alzheimer’s disease (AD). Astrocyte is the most numerous and the largest glial cell in the brain. By transporting energetic fuels such as lactate and ketones to neurons, astrocytes play a pivotal role in maintaining the cerebral energy homeostasis. Sodium butyrate (NaB), a type of short-chain fatty acid; its anti-inflammatory effect; and inhibition on histone deacetylases have been widely studied. Methods Spatial memory and cognitive ability of mice were assessed by using behavioral tests. Western blotting and ELISA kits were used to detect related protein levels and other biochemical markers, respectively. Objectives To prove the therapeutic effect of NaB on AD cognitive impairment and provide possible research ideas for mechanism exploration. Results Administration of NaB could improve the cognitive impairments induced by Aβ 25–35 in mice. Furthermore, NaB could promote the differentiation of astrocytes towards A2-neuron-protective subtype, astroglial mitochondrial function, and lactate shuttle between astrocytes and neurons. Conclusion These findings reveal the effect of sodium butyrate on astrocytes, which may improve the pathological status of AD and provide experimental basis for sodium butyrate treatment of AD.
研究领域:
神经科学
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药理学
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神经退行性疾病
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PubMed
高影响因子
Redox Biology
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2023
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IF 11.4
Dingbang Huang,Lixuan Chen,Qiuyi Ji,Yang Xiang,Qin Zhou,Kaiju Chen,Xiaoshun Zhang,Fei Zou,Xingmei Zhang,Zaihua Zhao,Tao Wang,Gang Zheng,Xiaojing Meng
Alzheimer's disease (AD) is a common neurodegenerative disease that is associated with multiple environmental risk factors, including heavy metals. Lead (Pb) is a heavy metal contaminant, which is closely related to the incidence of AD. However, the research on the role of microglia in Pb-induced AD-like pathology is limited. To determine the mechanism by which Pb exposure aggravates AD progression and the role of microglial activation, we exposed APP/PS1 mice and Aβ 1-42 -treated BV-2 cells to Pb. Our results suggested that chronic Pb exposure exacerbated learning and memory impairments in APP/PS1 mice. Pb exposure increased the activation of microglia in the hippocampus of APP/PS1 mice, which was associated with increased deposition of Aβ 1-42 , and induced hippocampal neuron damage. Pb exposure upregulated copper transporter 1 (CTR1) and downregulated copper P-type ATPase transporter (ATP7A) in the hippocampus of APP/PS1 mice and Aβ 1-42 -treated BV-2 cells. Moreover, Pb enhanced mitochondrial translocation of the mitochondrial copper transporter COX17, leading to an increase in mitochondrial copper concentration and mitochondrial damage. This could be reversed by copper-chelating agents or by inhibiting the mitochondrial translocation of COX17. The increased mitochondrial copper concentration caused by increased mitochondrial translocation of COX17 after Pb exposure may be related to the enhanced mitochondrial import pathway of AIF/CHCHD4. These results indicate that Pb induces the activation of microglia by increasing the concentration of copper in the mitochondria of microglia, and microglia release inflammatory factors to promote neuroinflammation, thus aggravating the pathology of AD. The present study provides new ideas for the prevention of Pb-induced AD.
研究领域:
神经科学
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毒理学
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神经退行性疾病
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PubMed
高影响因子
LIFE SCIENCES
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2019
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IF 3.448
Lingfeng Wang,Zhijun Pu,Mingxin Li,Kaixuan Wang,Lijuan Deng,Wei Chen
Aims Dauricine has been found that has significant neuroprotective effect on Alzheimer's disease (AD), but the mechanism is unclear, so we further investigated the possible mechanism of dauricine on AD. Main methods Cell counting kit-8 (CCK8) was applied to measure the cytotoxicity of dauricine on SH-SY5Y cells that overexpress the Swedish mutant form of human β-amyloid precursor protein (APPsw) and control cells (Neo). We used the Cu 2+ to induce oxidative damage on APPsw cells, then tested the effect of dauricine on the damage and relative factors including reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and superoxide dismutase (SOD) activity. The secretion level of amyloid beta 1–42(Aβ 1 – 42 ), protein expression of apoptosis-related factors and the components of nuclear factor erythroid 2-related factor 2 (Nrf2) pathway were determined by western blotting. Aβ 1 – 42 -transgenic Caenorhabditis elegans GMC101 , a model of AD, was applied to evaluate the neuroprotective effect of dauricine through the behavioral experiment and relative anti-oxidative tests. Key findings In vitro, dauricine decreased the secretion level of Aβ 1 – 42 , significantly reduced the level of Cu 2+ -induced ROS, and restored MMP and SOD activity in APPsw cells. Meanwhile, dauricine could suppress the activation of caspase-3 and to upregulate the expression of Bcl-2. Dauricine also regulated the proteins levels of Nrf2, and Kelch-like ECH-associated protein 1 (Keap1) that is necessary for the activation of Nrf2 in APPsw cell. As oxidative stress induced by Aβ or paraquat (PQ), dauricine showed protective effects in the survival experiment of GMC101 worms. Significance Those data revealed that dauricine has the pharmacological activity of anti-oxidative and anti-apoptosis, and shows the potential therapeutic value for AD.
研究领域:
神经科学
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药理学
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细胞生物学
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分子生物学
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PubMed
高影响因子
CHEMISTRY & BIODIVERSITY
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2022
·Vol. 20
·期 1
·e202200867
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IF 2.745
Huiyan Wang,Mengyang Su,Xuli Shi,Xiangyu Li,Xinyu Zhang,Aihong Yang,Rui Shen
Coumarins and their derivatives possessed a variety of biological activities and some of coumarin-based drugs have been approved by the US Food and Drug Administration. Alzheimer's disease (AD) has caused great losses to human society. However, due to its complex pathogenesis, the ideal therapeutic approach has not been found yet. Free radical scavenging activity which is one of the main activities of coumarin core structure is closely related to other anti-AD activities. Therefore, in this work coumarins were chosen as privileged lead compounds for the development of anti-AD drugs based on strategy of multi-target directed ligands (MTDLs). Derivatives 1 – 3 which could modulate multiple targets simultaneously, including ROS, cholinesterase, βamyloid (Aβ) aggregation, and metal dyshomeostasis were designed and for the first time synthesized. Their anti-AD activities were studied both in vitro and in silico . Results showed that 1 – 3 possessed potent antioxidant activities and 7-OH group did change the electron distribution of the molecule and enhance the antioxidant activities. They also have good inhibition activities on acetylcholinesterase (AChE) and Aβ aggregation and compound 1 had the strongest AChE inhibitory effect among the three compounds (AChE IC 50 =11.15 μM). Compound 1 – 3 could also selectively chelate with Cu 2+ and Al 3+ to regulate the metal homeostasis. In silico simulations, including molecular docking and prediction of ADMET performance, indicated that 1 – 3 could interact with target proteins and cross the blood brain barrier. In conclusion, 1 – 3 could be promising MTDLs applied as anti-AD candidate drugs. Graphical
研究领域:
药物化学
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神经科学
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有机合成
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PubMed
高影响因子
Natural Products and Bioprospecting
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2025
·Vol. 15
·期 1
·1-15
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IF 4.9
Huang Wen,Liu Yihan,Jiang Haixin,Guo Dongxue,Song Yi,Wang Junqi,Li Luqi,Zhang Qiang
Bioactive compounds from food-compatible medicinal herbs have shown promise as preventive agents against age-related neurodegenerative conditions, particularly Alzheimer’s disease (AD). The present work aimed to find Lobetyolin as a new suppressor of Aβ aggregation and its interventions on abnormal metabolism in AD. Aβ-expressing Caenorhabditis elegans (strain CL4176) and wild-type worms were employed to evaluate paralysis onset, lifespan, cerebral Aβ deposition, and intracellular reactive oxygen species (ROS) after Lobetyolin administration. Untargeted ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS) metabolomics coupled with RNA-seq transcriptomics was carried out to profile systemic metabolic and gene-expression changes. Differential metabolites and transcripts were subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and pathway-impact analyses; hub targets were prioritized by integrating enrichment scores with in-silico docking. Lobetyolin (12.5–50 µM) markedly protected C. elegans from Aβ-driven toxicity and oxidative stress. In CL2006 worms, β-amyloid deposits fell by 54.8 ± 9.4%, while paralysis in CL4176 was delayed by 20.9 ± 4.5%. Lifespan increased by up to 18.2% in CL4176 and 25.0% in wild-type N2 worms. Concomitantly, intracellular ROS declined maximally by 28.1 ± 8.9% (N2) and 22.4 ± 3.8% (CL4176). Integrative metabolomic–transcriptomic analyses, validated by RT-qPCR, revealed selective remodeling of glutathione metabolism: gst-38 expression was suppressed, whereas gst-1 was elevated. Lobetyolin confers neuroprotective and geroprotective benefits in vivo , primarily through reprogramming glutathione-centered redox metabolism and selectively modulating glutathione-S-transferases (GST) isoforms. These findings position Lobetyolin as a promising dietary lead compound for AD prevention and healthy aging interventions. Graphical
研究领域:
神经科学
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药理学
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代谢组学
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转录组学
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衰老研究
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天然产物化学
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PubMed
高影响因子
NEUROSCIENCE
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2023
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IF 3.3
Lu-Lu Lin,Gui-Jun Song,Hui Zhang,Yan Yin,Shi-Meng Xin,Li Ding,Yu Li
Alzheimer's disease (AD) is a serious neurodegenerative disease characterized by amyloid-β (Aβ) aggregation and neuroinflammation. G-protein-coupled receptor 34 (Gpr34) was found highly expressed in the hippocampus of APP/PS1 mice. However, its role in AD remains unclear. Herein, the role of Gpr34 as well as its molecular mechanism was explored. Data in GSE85162 were analyzed and the differently expressed genes in the hippocampus tissues of APP/PS1 mouse model of AD were subjected to GO, KEGG and GSEA enrichment analyses. APP/PS1 mice were used as an animal model of AD and the cognitive impairment was evaluated by a water maze test. The level of Gpr34 in hippocampus and BV-2 cells as well as the activation of ERK/NF-κB signal was determined by quantitative real-time PCR, western blot or immunofluorescence. Our results showed that, in BV-2 cells exposed to Aβ 1-42 , Gpr34 knockdown decreased the levels of TNF-α, IL-1β, IL-6 and iNOS and suppressed the activation of ERK/NF-κB signal. Moreover, the Gpr34-overexpression-induced activation of ERK/NF-κB signal and up-regulated levels of TNF-α, IL-1β, IL-6 and iNOS were abolished by FR180204, an ERK inhibitor. On the other hand, the in vivo study showed that Gpr34 knockdown ameliorated the cognitive impairment in APP/PS1 mice, decreased the levels of TNF-α, IL-1β and IL-6, the activation of microglia and ERK/NF-κB signal. In conclusion, Gpr34 knockdown relieved cognitive deficits in APP/PS1 mice and suppressed neuroinflammation and microglial activation, maybe via the ERK/NF-κB signal. It is indicated that the high level of Grp34 in hippocampus may contribute to the pathogenesis of AD.
研究领域:
神经科学
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分子生物学
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神经退行性疾病
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PubMed
高影响因子
BIOSENSORS & BIOELECTRONICS
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2013
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IF 5.437
Lin Liu,Feng Zhao,Fengji Ma,Liping Zhang,Suling Yang,Ning Xia
β-Amyloid (Aβ) peptides are believed to be important for the diagnosis and prognosis of Alzheimer's disease (AD) serving as reliable molecular biomarkers. In this work, we reported a simple and sensitive electrochemical strategy for the detection of total Aβ peptides using gold nanoparticles modified with Aβ(1–16)-heme (denoted as Aβ(1–16)-heme-AuNPs). Monoclonal antibody (mAb) specific to the common N-terminus of Aβ was immobilized onto gold electrode for the capture of Aβ(1–16)-heme-AuNPs. The anchored Aβ(1–16)-heme-AuNPs showed strong electrocatalytic O 2 reduction. Pre-incubation of the mAb-covered electrode with native Aβ decreased the amount of Aβ(1–16)-heme-AuNPs immobilized onto the electrode, resulting in the decrease of the reduction current of O 2 to H 2 O 2 . The competitive assay is sensitive and selective to Aβ peptides. The voltammetric responses were found to be proportional to the concentrations of Aβ ranging from 0.02 to 1.50 nM, and a detection limit of 10 pM was achieved. To demonstrate the viability of the method for the analysis of Aβ in real sample, artificial cerebrospinal fluid (aCSF) containing Aβ(1–40), Aβ(1–42) and Aβ(1–16) was tested. We believe that the method would offer a useful means for quantifying Aβ in a biological matrix, and be valuable in the design of new types of electrochemical biosensors for the detection of peptides and proteins.
研究领域:
生物医学
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神经科学
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分析化学
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PubMed
高影响因子
JOURNAL OF ALZHEIMERS DISEASE
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2025
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IF 3.1
Yanyu Zhai,Kaili Lu,Yuan Yuan,Ziyao Zhang,Lixia Xue,Fei Zhao,Xiaofeng Xu,Hongmei Wang
BackgroundAlzheimer's disease (AD) causes cognitive function disorder and has become the preeminent cause of dementia. Glucagon-like peptide-1 (GLP-1) receptor agonists, semaglutide, have shown positive effects on promoting the cognitive function. However, research about the mechanism of semaglutide as a therapeutic intervention in AD is sparse.ObjectiveThis study was to investigate the therapeutic efficacy of semaglutide in a transgenic mouse model of AD pathology and explored the detailed mechanism by semaglutide modulated neuroinflammatory processes.MethodsMale amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice were treated with semaglutide or vehicle for 8 weeks. Morris water maze test was used to assess the therapeutic efficacy of semaglutide on recognition function. Pathology analysis was performed to detect the deposition of amyloid plaques. High-throughput sequencing analysis was applied to specify the mechanism. Microglia and astrocyte activation were assessed with immunofluorescent staining. Inflammation cytokine levels were evaluated with enzyme-linked immunosorbent assay (ELISA). Related proteins and pathway were evaluated with western blot.ResultsSemaglutide treatment attenuated Aβ accumulation and enhanced cognitive function in APP/PS1 transgenic mice. Through transcriptomic profiling, immunohistochemical staining, and ELISA, semaglutide was substantiated to inhibit the overactivation of microglia and astrocytes, as well as to curtail the secretion of inflammatory mediators. Furthermore, semaglutide robustly activated AMP-activated protein kinase (AMPK) and suppressed the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling cascade, thus reducing the Aβ deposition and dampening the inflammatory cascade.ConclusionsThe results demonstrated that semaglutide mitigated neuroinflammation and decelerated the advance of AD in APP/PS1 transgenic mice.
研究领域:
神经科学
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药理学
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分子生物学
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神经退行性疾病
·
炎症研究
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PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2024
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IF 6.9
Xin Tan,Rui Xu,Ai-Pei Li,Dan Li,Yun Wang,Qian Zhao,Li-Ping Long,Yu-Zhou Fan,Chen-Xiao Zhao,Yan Liu,Sheng-Hong Li
1,8-Cineole is a bicyclic monoterpene widely distributed in the essential oils of various medicinal plants, and it exhibits significant anti-inflammatory and antioxidant activities. We aimed to investigate the therapeutic effect of 1,8-cineole on anti-Alzheimer's disease by using transgenic Caenorhabditis elegans models. Our studies demonstrated that 1,8-cineole significantly relieved A β 1–42 -induced paralysis and exhibited remarkable antioxidant and anti-A β 1–42 aggregation activities in transgenic nematodes CL4176, CL2006 and CL2355. We developed a 1,8-cineole/cyclodextrin inclusion complex, displaying enhanced anti-paralysis, anti-A β aggregation and antioxidant activities compared to 1,8-cineole. In addition, we found 1,8-cineole treatment activated the SKN-1/Nrf-2 pathway and induced autophagy in nematodes. Our results demonstrated the antioxidant and anti-Alzheimer's disease activities of 1,8-cineole, which provide a potential therapeutic approach for Alzheimer's disease.
研究领域:
神经科学
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药理学
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分子生物学
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PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2024
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IF 13.3
Zhenjie Zhang,Chenhao Wang,Jingzhang Wang,Wei Wei,Zhengyu Wang,Xian Li,Anne Ailina Li,Lianqun Zhou,Qing Wang,Hui Kong
Beta-amyloid 42 (Aβ-42) peptide is an essential biomarker for Alzheimer's disease (AD) diagnosis. This study presents high sensitivity and stability sensors for Aβ-42 peptide detection, along with an integrated handheld analysis and display device. The sensors, with a wide response range and high accuracy, capable of measuring Aβ-42 peptide concentration at the femtogram level, could have enabled early screening for AD. Employing an in-situ grown three-dimensional sensor, the specific surface area of the sensor was increased by 200 % which, thereby, provided more antibody binding sites to enhance detection accuracy. This electrochemical sensor demonstrated a broad linear response range from 4.5 × 10 −8 pg/mL to 4.5 × 10 2 pg/mL and could accurately determine the concentration of spiked analytes (including artificial saliva, human plasma, and human blood). Furthermore, the sensor exhibited satisfactory stability, with only a 5 % sensitivity loss after 35 days of storage at 4 °C. Additionally, this handheld Aβ-42 peptide testing device incorporates a display for result delivery. Such innovative technology could fill the gap in the market for portable testing instruments and could provide an efficient and reliable solution for early AD screening.
研究领域:
生物传感器
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神经退行性疾病
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电化学
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医疗器械
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分析化学
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高影响因子
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