Journal of Translational Medicine
·
2023
·Vol. 21
·期 1
·1-15
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IF 7.4
Wan Can,Liu Xiao-Qi,Chen Mei,Ma Hui-Han,Wu Guang-Liang,Qiao Li-Jun,Cai Ye-Feng,Zhang Shi-Jie
Background The disruption of blood-brain barrier (BBB), predominantly made up by brain microvascular endothelial cells (BMECs), is one of the characteristics of Alzheimer’s disease (AD). Thus, improving BMEC function may be beneficial for AD treatment. Tanshinone IIA (Tan IIA) has been proved to ameliorate the cognitive dysfunction of AD. Herein, we explored how Tan IIA affected the function of BMECs in AD.Methods Aβ1–42-treated brain-derived endothelium cells.3 (bEnd.3 cells) was employed for in vitro experiments. And we performed molecular docking and qPCR to determine the targeting molecule of Tan IIA on Sirtuins family. The APPswe/PSdE9 (APP/PS1) mice were applied to perform the in vivo experiments. Following the behavioral tests, protein expression was determined through western blot and immunofluorescence. The activities of oxidative stress-related enzymes were analyzed by biochemically kits. Nissl staining and thioflavin T staining were conducted to reflect the neurodegeneration and Aβ deposition respectively.Results Molecular docking and qPCR results showed that Tan IIA mainly acted on Sirtuin1 (SIRT1) in Sirtuins family. The inhibitor of SIRT1 (EX527) was employed to further substantiate that Tan IIA could attenuate SIRT1-mediated endoplasmic reticulum stress (ER stress) in BMECs. Behavioral tests suggested that Tan IIA could improve the cognitive deficits in APP/PS1 mice. Tan IIA administration increased SIRT1 expression and alleviated ER stress in APP/PS1 mice. In addition, LRP1 expression was increased and RAGE expression was decreased after Tan IIA administration in both animals and cells.Conclusion Tan IIA could promote Aβ transportation by alleviating SIRT1-mediated ER stress in BMECs, which ameliorated cognitive deficits in APP/PS1 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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细胞生物学
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DOI
PubMed
高影响因子
ZEITSCHRIFT FUR ANORGANISCHE UND ALLGEMEINE CHEMIE
·
2022
·Vol. 648
·期 11
·e202200070
·
IF 1.414
Yusi Yao,Wenhui Li,Qiuqin Han,Guanglei Lv,Chunxia Li,Anyang Sun
Amyloid-β (Aβ) fibrils play a pivotal role in driving neuroinflammation and the progression of tau pathology in Alzheimer's disease (AD). In addition, Aβ oligomers are presumed to be closely associated with pathogenesis of AD. Currently, although a few Aβ antibodies are available, fluorescent probes still play an important role in detecting Aβ pathology. Herein, we designed and synthesized a pyridyl zinc chelate KZ and tested its potential specificity to Aβ species. The probe KZ showed a good binding to fibrillar Aβ aggregates and an excellent anti-interference feature in vitro. Importantly, KZ could display a subset of Aβ deposits recognized by OC antibody in brain sections of AD mouse models. Thus, this probe KZ could be used as a sensitive tracer for detecting Aβ fibrils or/and fibrillar oligomers.
研究领域:
神经科学
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化学
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生物学
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医学
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DOI
高影响因子
BIOMATERIALS
·
2026
·
IF 13.6
Xinzhu Sun,Yilong Xi,Yun Chen,Jianping Zhou,Jiang Ni,Yang Ding,Huaqing Zhang
Amyloid-β (Aβ) clearance holds promise in Alzheimer's disease (AD) treatment, but the clinical application is limited by poor clearance efficacy and microglial inflammatory cascade caused by overloaded Aβ degradation. In this study, a polymeric lipoprotein-curcumin nanoscavenger (CP/ Man Disc-Cur) with dysfunctional microglia-specific targeting capability is designed to synergistically promote Aβ clearance and inhibit microglial inflammatory cascade. For preparation, curcumin is post-encapsulated into mannose-modified Disc ( Man Disc-Cur), followed by assembly with chitosan derivatives (CP) to obtain CP/ Man Disc-Cur. After intranasal administration and triggered by the nasal acidic microenvironment, CP/ Man Disc-Cur is depolymerized into Man Disc-Cur and protonated CP that adheres to reversibly open the tight junctions, promoting Man Disc-Cur penetration into the brain via the olfactory pathway. Thereafter, Man Disc-Cur captures Aβ oligomer with a high binding affinity (K D = 5.90 × 10 −8 M) and selectively targets dysfunctional microglia where Aβ catabolism is accelerated with inflammation inhibition by curcumin. After nasal treatment of CP/ Man Disc-Cur for 4 weeks, Aβ burden, microglial inflammation, and memory deficits of APPswe/PS1dE9 transgenic AD mice are significantly attenuated without the obvious side effects. Collectively, this study provides a promising strategy for synergistically improving Aβ clearance and inhibiting microglial inflammatory cascade for enhanced AD treatment.
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高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Ziqi Gu,Hang Zhao,Yilan Song,Yiduo Kou,Wanting Yang,Ye Li,Xiang Li,Ling Ding,Zihui Sun,Jing Lin,Qi Wang,Xi Li,Xu Yang,Xuerong Huang,Chuang Yang,Zhiqian Tong
Alzheimer’s disease (AD), which is a prevailing type of dementia, presents a significant global health concern. The current therapies do not meet clinical expectations. Amyloid-beta (Aβ) has been found to induce endogenous formaldehyde (FA) accumulation by inactivating FA dehydrogenase (FDH); in turn, excessive FA triggers Aβ aggregation that eventually leads to AD onset. Hence, scavenging FA by astaxanthin (ATX, a strong exogenous antioxidant) may be pursued as a promising disease-modifying approach. Here, we report that liposomal nanoparticles coupled with PEG (PEG-ATX@NPs) could enhance water-solubility of ATX and alleviate cognitive impairments by scavenging FA and reducing Aβ deposition. To enable drug delivery to the brain, liposomes were used to encapsulate ATX and then coupled with PEG, which produced liposomal nanoparticles (PEGATX@NPs) with a diameter of <100 nm. The PEG-ATX@NPs reduced Aβ neurotoxicity by both degrading FA and reducing FA-induced Aβ assembly in vitro. Intraperitoneal administration of PEG-ATX@NPs in APPswe/PS1dE9 mice (APP/PS1, a familial model of AD), not only decreased the levels of brain FA and malondialdehyde (MDA, a typical product of oxidative stress), but also attenuated both intracellular Aβ oligomerization and extracellular Aβ-related senile plaque (SP) formation. These pathological changes were accompanied by rescued ability of spatial learning and memory. Collectively, PEG-ATX@NPs improved the water-solubility, bioavailability, and effectiveness of ATX. Thus, it has the potential to be developed as a safe and effective strategy for treating AD.
研究领域:
神经科学
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药理学
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纳米技术
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痴呆症研究
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PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
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2020
·
IF 4.352
Yan Wang,Meiling Lian,Xiaoyu Xiu,Zhiwen Zhang,Liping Song,Shengzhou Wu
Metabolism of β-amyloid is critical for healthy brain. Decreased clearance of β-amyloid is associated with ensued accumulation of amyloid peptide, culminating in formation of senile plaques, a neuropathological hallmark of Alzheimer's disease(AD). Apolipoprotein E ( APOE ), a lipoprotein for phospholipid and cholesterol metabolism, is predominantly synthesized by glia in the central nervous system, controlling Aβ aggregation and metabolism. By use of stereotactic injection and a Morris water maze, we found that delivery of Dicer1-expressing adenovirus into the hippocampus of an animal model of AD mice APPswe/PSEN1deltaE9 significantly improved spatial memory. The effect was associated with reduced amyloid peptides in the hippocampus which were analyzed with immunofluorescence and enzyme-linked immunosorbent assay. With western blot, quantitative real-time PCR, fluorescence in situ hybridization, and northern blot,Dicer1 overexpression increased apolipoprotein E (APOE) and concomitantly decreased B2 RNA in the hippocampus of the AD mice and in astrocyte cultures whereas transfection of B2 Mm2 RNA decreased APOE mRNA and protein levels in astrocyte cultures. Further, human or mouse APOE mRNA was found containing Alu RNA or its equivalent, B2 Mm2 RNA, locating downstream of its 3′-untranslated region (UTR), respectively. The 3′-UTR or 3′-UTR in conjunction with the downstream Alu/B2 RNA were cloned into a luciferase reporter; with dual-luciferase assay, we found that simultaneous transfection of Dicer1 siRNA or Alu/B2 RNA decreased the corresponding luciferase activities which suggest that Alu RNA mediated APOE mRNA degradation. Altogether, Dicer1 expression mediated amyloid peptide clearance by increasing APOE via blocking B2 RNA-mediated APOE mRNA degradation.
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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基因调控
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DOI
PubMed
高影响因子
Food & Function
·
2021
·Vol. 12
·期 3
·1219-1231
·
IF 5.396
Hui Li,Xiaoxuan Yu,Chenxi Li,Lei Ma,Zhenyu Zhao,Shuwen Guan,Liping Wang
Caffeic acid (CA), a derivative of cinnamic acid, exists in various vegetables and fruits. Natural compounds as beneficial antioxidants play an important role in the research of Alzheimer's disease (AD). In this study, we evaluated the effects of CA against AD using the C. elegans models of AD. We found that CA significantly alleviated Aβ-induced toxicity, increased lifespan, decreased body paralysis, and improved reproductive defects. Also, CA treatment increased resistance to heat and oxidative stress in N2 and CL4176. Moreover, reactive oxygen species (ROS) levels and polyglutamine (polyQ40) aggregate formation were reduced. Furthermore, the mechanistic studies revealed that CA activated transcription factor DAF-16 and its downstream targets SOD-3 and GST-4 to protect against Aβ toxicity. Also, the heat shock proteins hsf-1 and hsp-16.2 mRNA were up-regulated in CL4176. Moreover, CA activated the mRNA expression of lgg-1. Lastly, the KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis of RNA-seq data revealed that there was a significant change in the metabolism-related pathways. Overall, these results suggested an underlying mechanism of action of CA in treating AD at an organism level.
研究领域:
神经科学
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分子生物学
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药理学
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PubMed
高影响因子
BIOORGANIC CHEMISTRY
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2018
·
IF 3.929
Qingbo Liu,Jie Wang,Bin Lin,Zhuo-Yang Cheng,Ming Bai,Shaochun Shi,Xiao-Xiao Huang,Shao-Jiang Song
Alzheimer’s disease (AD) is characterized by the progressive accumulation of extracellular β -amyloid (A β ) aggregates. Recently, lignans and phenylpropanoids are attracting increasing attention to discovery useful agents of inhibition on A β aggregation. In the present study, to develop potential agents for slowing the progression of AD, Prunus tomentosa seeds were selected as a raw material for bioactive compounds, which led to the separation of two pairs of new enantiomeric lignans and phenylpropanoids using chiral HPLC. The planar structures of these compounds were elucidated by spectroscopic data analyses. And their absolute configurations were determined by comparing of experimental and calculated electronic circular dichroism (ECD). The biosynthesis pathway was also discussed. Additionally, the inhibitory activity on A β aggregation of all optical pure compounds was tested by thioflavin T (ThT) assay. The isolates ( 1a , 1b , 2a and 2b ) showed more potent inhibitory activity than positive control curcumin with inhibitory rate of 73.89 ± 3.41% 78.69 ± 1.50%, 63.25 ± 2.68%, and 67.13 ± 0.90% at 20 μM, respectively. More importantly, the inhibition profiles were explained by molecular dynamics and docking simulation studies.
研究领域:
药理学
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植物化学
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神经科学
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DOI
PubMed
高影响因子
Current Medical Science
·
2026
·
IF 2
Liu Xin,Xu Qing-qing,Zhang Yi-bo,Yuan Shi-yu,Huang Wen-li,Pi Ming-shan,Xiong Qi,Gui Yu-ran,Deng Shi-chao,Wan Ling,Xiao Yi-fan,Wang Xiao-chuan,Shu Xi-ji,Xia Yi-yuan
Objective Alzheimer’s disease (AD) is a progressive neurodegenerative disease associated with metabolic dysregulation. This study aimed to investigate the role of homogentisic acid (HGA), a tyrosine metabolite, in AD pathogenesis and explore its potential as a noninvasive diagnostic biomarker. Methods Human saliva samples from AD patients and controls were analyzed. In vivo experiments were conducted using APP/PS1 (Aβ-driven) and P301S (tauopathy-focused) mouse models, which received exogenous HGA via gavage. Key techniques included behavioral tests (Morris water maze, novel object recognition, fear conditioning), Western blot, immunofluorescence, real-time PCR, and mass spectrometry to assess cognitive function, blood–brain barrier (BBB) integrity, Aβ aggregation, synaptic protein expression, and HGA metabolism. In vitro experiments were performed on HT22, SY5Y cells, and primary brain microvascular endothelial cells (BMECs) to verify HGA’s direct effects. Results Salivary HGA levels were higher in AD patients than in controls, correlating with BBB impairment. Exogenous HGA significantly exacerbated cognitive deficits, BBB leakage, Aβ deposition, and loss of synaptic proteins (PSD93, synaptophysin) in mice, with effects more pronounced in the APP/PS1 than in the P301S model. In vitro, HGA exerted dose-dependent neurotoxicity, promoted Aβ aggregation, and downregulated tight junction proteins (claudin-5, occludin, ZO-1) in BMECs. Mechanistically, AD patients showed reduced expression of HGA-metabolizing enzymes (homogentisate 1,2-dioxygenase, maleylacetoacetate isomerase) and downstream metabolites, indicating impaired HGA catabolism. These findings confirm HGA promotes AD progression via two mutually reinforcing pathways: (1) accelerating Aβ aggregation and synaptic dysfunction; (2) disrupting BBB integrity through downregulating tight junction proteins. Conclusion This study identifies salivary HGA as a potential noninvasive biomarker and highlights targeting HGA metabolism or BBB protection as promising strategies for early AD intervention.
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高影响因子
Journal of Neuroinflammation
·
2026
·Vol. 23
·期 1
·90
·
IF 11.5
Tang Fenglin,Li Yufeng,Bai Xue,Zhu Zhongmou,Dong Hongwei,Chen Jianhui,Ye Bo,Yuan Meng,Wu Qilong,Fu Weishan,Zhang Yuan,Wang Chao
Alzheimer’s disease (AD) is the most common neurodegenerative disorder, with circadian rhythm disturbances strongly linked to its pathogenesis. The choroid plexus (ChP) is a circadian-regulated structure in the brain ventricles, but the role of the core clock gene brain and muscle ARNT-like protein 1 ( BMAL1 ) in ChP in relation to AD pathology remains unclear. Here, we report that knockdown of Bmal1 in ChP epithelial cells of 5xFAD mice alleviates amyloid-β (Aβ) pathology, primarily by improving the function of astrocytes and border-associated macrophages (BAMs), with the latter potentially mediated by the upregulation of the secreted protein glutathione peroxidase 3 (GPX3), which reduces lipid peroxidation in BAMs. Collectively, our findings establish the ChP-driven BMAL1-GPX3 axis as a new Aβ clearance mechanism, with GPX3 representing a promising therapeutic target. These findings provide new mechanistic insights into AD and suggest innovative treatment approaches.
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高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2024
·
IF 12.2
Xiaoli Gou,Yongchun Fu,Juan Li,Juan Xiang,Minghui Yang,Yi Zhang
Nanoplastics , widely existing in the environment and organisms, have been proven to cross the blood-brain barrier, increasing the incidence of neurodegenerative diseases like Alzheimer’s disease (AD). However, current studies mainly focus on the neurotoxicity of nanoplastics themselves, neglecting their synergistic effects with other biomolecules and the resulting neurotoxicity. Amyloid β peptide (Aβ), which triggers neurotoxicity through its self-aggregation, is the paramount pathogenic protein in AD. Here, employing polystyrene nanoparticles (PS) as a model for nanoplastics, we reveal that 100 pM PS nanoparticles significantly accelerate the nucleation rate of two Aβ subtypes (Aβ 40 and Aβ 42 ) at low concentrations, promoting the formation of more Aβ oligomers and leading to evident neurotoxicity. The hydrophobic surface of PS facilitates the interaction of hydrophobic fragments between Aβ monomers , responsible for the augmented neurotoxicity. This work provides consequential insights into the modulatory impact of low-dose PS on Aβ aggregation and the ensuing neurotoxicity, presenting a valuable foundation for future research on the intricate interplay between environmental toxins and brain diseases.
研究领域:
神经科学
·
环境科学
·
医学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF TOXICOLOGY
·
2025
·
IF 1
Yanhong Fu,Jiafa Zhang,Canhong Yang,Yuanyuan Wang,Yunzhu Yang,Pingming Qiu,Weibing Xie,Shufen Zhang,Tianming Lǚ
Dimethyl sulfoxide (DMSO) is commonly used as a solvent for preparing amyloid-beta (Aβ) peptides implicated in Alzheimer’s disease. While considered relatively non-toxic at low concentrations, DMSO itself may exert biological effects that could confound experimental outcomes, especially for weakly cytotoxic substances like Aβ. Seven brain cell types (BV-2, N2a, SH-SY5Y, U87, neurons, astrocytes, microglia) were treated with varying DMSO concentrations or Aβ1-42 oligomers/protofibrils/fibrils prepared using DMSO. Cell viability was assessed by CCK-8 and LDH assays. Matched DMSO controls were prepared alongside Aβ treatments to delineate solvent effects. Low DMSO concentrations (0.0625-0.015625%) exhibited hormetic cytoprotective and growth-promoting effects, while higher concentrations (≥2%) were cytotoxic. Importantly, these hormetic solvent effects confounded the measurement of Aβ cytotoxicity. By accounting for matched DMSO controls, the study revealed that Aβ fibril toxicity may have been underestimated due to the cytoprotective solvent effects of low DMSO concentrations used in their preparation. In conclusion, DMSO exhibits complex hormetic dose-responses that can significantly influence experimental outcomes, especially for weakly cytotoxic agents like Aβ. Rigorous solvent controls are crucial to delineate genuine substance effects from potential solvent confounds and avoid erroneous interpretations.
研究领域:
神经科学
·
细胞生物学
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药理学
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DOI
PubMed
高影响因子
RSC Advances
·
2019
·Vol. 9
·期 32
·18308-18319
·
IF 3.049
Mengying Wei,Yuanyuan Liu,Zifeng Pi,Kexin Yue,Shizhe Li,Mingxin Hu,Zhiqiang Liu,Fengrui Song,Zhongying Liu
Alzheimer's disease (AD) has become one of the major diseases endangering the health of the elderly. Clarifying the features of each AD animal model is valuable for understanding the onset and progression of diseases and developing potential treatments in the pharmaceutical industry. In this study, we aimed to clarify plasma metabolomics and neurotransmitter dysfunction in the process of AD model rat induced by amyloid beta 25-35 (Aβ 25-35). Firstly, Morris Water Maze (MWM) test was used to investigate cognitive impairment in AD rat after 2, 4 and 8 weeks of modelling. Based on this, the effects on levels of AD-related enzymes and eight neurotransmitters were analyzed. And plasma metabolomics analysis based on ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) was used to research the metabolic disturbances in the process of AD rat. The results shown the injury on the spatial learning ability of AD rats was gradually aggravated within 4 weeks, reached the maximum at 4 weeks and then was stable until 8 weeks. During 8 weeks of modeling, the levels of enzymes including β-secretase, γ-secretase, glycogen synthase kinase-3β (GSK-3β), acetyl cholinesterase (AchE) and nitric oxide synthase (NOS) were significant increased in the plasma of AD rats. The neurotransmitter dysfunction was mainly involved in γ-aminobutyric acid (GABA), acetyl choline (Ach), glutamic acid (Glu), 5-hydroxytryptamine (5-HT), dopamine (DA) and norepinephrine (NE). 17 endogenous metabolites correlated with AD were successfully detected in the metabolomics analysis. These metabolites were mainly involved in fatty acids, sphingolipids, and sterols metabolisms, vitamin metabolism, and amino acid metabolism. These metabolites might be the potential biomarkers that correctly mark different stages of AD. The study on peripheral plasma indices reflecting the process of AD laid the foundation for understand the pathophysiology of AD and find an effective and radical cure. And the rules of endogenous metabolic disorder in AD rats also have a certain guiding significance for the future study of food–drug interactions at different stages of AD.
研究领域:
神经科学
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代谢组学
·
药理学
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PubMed
高影响因子
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