MATERIALS & DESIGN
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2025
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IF 7.9
Ye-Cheng Wang,Si-Cong Bai,Xue-Ying Hu,Jia-Yi Lin,Wei-Lin Ye,Huan-Zhang Xie,Liu Hong,Gao Li
To slow the progression of Alzheimer’s disease (AD), eliminating amyloid β (Aβ) or inhibiting its abnormal aggregation has emerged as a promising strategy. Among the molecules developed to inhibit Aβ aggregation, gold nanoclusters (AuNCs) stand out due to their excellent biocompatibility and high efficiency in modulating Aβ aggregation. However, the currently reported AuNCs often lack specificity toward Aβ, which may limit their in vivo applications. In this study, we synthesized a novel gold nanocluster (AuCRHA1) functionalized with the peptide CRHRHKLVFF to achieve specific recognition of Aβ. Our results demonstrated that AuCRHA1 effectively inhibited Aβ aggregation and reduced its cytotoxicity in complex solutions, underscoring the robustness of our design. By combining isothermal titration calorimetry results with mathematical modeling, molecular docking, and molecular dynamics simulation, we identified two main inhibitory roles of AuCRHA1: binding to free Aβ monomers to reduce the effective Aβ concentration and depolymerizing mature fibrils. Moreover, treatment with AuCRHA1 significantly extended the lifespan of Caenorhabditis elegans , an AD model organism. Collectively, this work highlights the potential of AuCRHA1 as a promising agent for inhibiting Aβ aggregation and its application in preventing or treating AD.
研究领域:
生物化学
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纳米医学
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神经科学
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DOI
高影响因子
ANALYTICAL CHEMISTRY
·
2020
·
IF 6.785
Yan Zhou,Jia Liu,Tingting Zheng,Yang Tian
The aggregation of Aβ has been reported to closely correlate with Alzheimer’s disease (AD). However, clear monitoring of the entire aggregation process of Aβ from monomer to fibril has been scarcely reported until now. Herein, we developed a label-free ratiometric surface enhanced Raman spectroscopic (SERS) platform for real-time monitoring of the entire process of Aβ aggregation in neurons and brain tissues. Different gold nanoparticles, generated in situ with Aβ monomer and fibril as templates separately, were served as effective SERS substrates to achieve a high sensitivity with a limit of detection (LOD) down to 70 ± 4 pM and 3.0 ± 0.5 pM for Aβ40 monomer and fibrils, respectively. Besides, the introduction of ratiometric determination of Aβ monomer and fibril (I1244/I1268) realized real-time monitoring of the entire aggregation process of Aβ monomer with high accuracy and selectivity against other proteins and amino acids. The significant analytical performance of the developed platform, together with good biocompatibility, long-term stability, and remarkable spatial resolution, enabled the present SERS platform imaging and real-time monitoring and imaging of Aβ aggregation influenced by different metal ions (Cu2+, Zn2+, and Fe3+) in neurons and brain tissues at the single cell level. Our results suggested that Cu2+ and Zn2+ ion of low concentration (10 μM) promoted fibril formation, while Fe3+ and Zn2+ of high concentration (100 μM) showed inhibition of fibrosis.
研究领域:
生物化学
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医学
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神经科学
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DOI
PubMed
高影响因子
Communications Chemistry
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2025
·Vol. 8
·期 1
·1-12
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IF 6.2
Bai Si-Cong,Wang Ye-Cheng,Ye Wei-Lin,Wu Sheng-Yen,Jia Lee,Hong Liu,Xie Huan-Zhang,Li Gao
Abnormal amyloid beta (Aβ) aggregation is a key factor in Alzheimer’s disease (AD) pathology. Despite efforts to develop Aβ aggregation inhibitors, efficient screening strategies remain limited. Here, we initially applied structure-based virtual screening to target Aβ fibril ends, aiming to identify compounds that could effectively combat AD neurodegeneration. Using this approach, we screened a traditional Chinese medicine library with thousands of compounds, and selected high-scoring hits likely to inhibit fibril elongation or promote fibril depolymerization. Forsythoside A emerged as the most potent inhibitor, effectively reducing Aβ 40 aggregation and disassembling pre-formed fibrils, as confirmed through biophysical assays and surface plasmon resonance analysis. Chemical kinetics further elucidated its inhibitory mechanism. In Caenorhabditis elegans , forsythoside A alleviated Aβ-induced toxicity and extended the lifespan of the AD transgenic models. Further virtual screening and experimental validation using a CNS-penetrant compound library confirmed the robustness of our strategy. Our study underscores the effectiveness of virtual screening in the identification of Aβ aggregation inhibitors and emphasizes the critical significance of targeting fibril ends.
研究领域:
结构生物学
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药物筛选
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神经科学
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生物物理学
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DOI
PubMed
高影响因子
LANGMUIR
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2020
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IF 3.557
Junnan Yang,Wei Liu,Yan Sun,Xiaoyan Dong
Deposition of amyloid-β (Aβ) aggregates in the brain is a main pathological hallmark of Alzheimer’s disease (AD), so inhibition of Aβ aggregation has been considered as a promising strategy for AD prevention and treatment. Black phosphorus (BP) is a 2D nanomaterial with high biocompatibility and unique biodegradability, but its potential application in biomedicine suffers from the rapid degradability and unfunctionability. To overcome the drawbacks and broaden its application, we have herein designed an Aβ inhibitor (LK7)-coupled and polyethylene glycol (PEG)-stabilized BP-based nanosystem. The PEGylated-LK7-BP nanosheets (PEG-LK7@BP) not only exhibited a good stability but also demonstrated a significantly enhanced inhibitory potency on Aβ42 fibrillogenesis in comparison with its counterparts. This elaborately designed PEG-LK7@BP stopped the conformational transition and suppressed the fibrillization of Aβ42, so it could completely rescue cultured cells from the toxicity of Aβ42 (by increasing the cell viability from 72 to 100%) at 100 μg/mL. It is considered that PEG-LK7@BP could bind Aβ species by enhanced electrostatic and hydrophobic interactions and thus efficiently alleviated Aβ–Aβ interactions. Meanwhile, the coupled LK7 on the BP surface formed a high local concentration that enhanced the affinity between the nanosystem and Aβ species. Finally, PEG could improve the stability and dispersibility of the nanoplatform to make it show an increased inhibitory effect on the amyloid formation. Hence, this work proved that PEG-LK7@BP is a promising nanosystem for the development of amyloid inhibitors fighting against AD.
研究领域:
生物医学
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纳米材料科学
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神经退行性疾病研究
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DOI
PubMed
高影响因子
NEUROSCIENCE LETTERS
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2023
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IF 2.5
Rong Wei,Jun-Qiu He,Wen-Hua Chen,Kin Yip Tam
Alzheimer's disease (AD) patients exhibit neuropathological features, such as amyloid-beta (Aβ) plaques and neurogenic fibrillary tangles. These features are thought to play important pathogenic roles, including neuronal dysfunction and apoptosis in the disease progression. Herein, we systematically evaluated a previously reported dual-target isoquinoline inhibitor ( 9S ) for cholinesterase and Aβ aggregation in in vitro and in vivo models of AD. 9S exhibited neuroprotective effects in Aβ-induced and PHF6-induced PC12 cell models as well as in an okadaic acid-induced SH-SY5Y cell model, which were due to attenuated neuronal apoptosis through modulations of GSK-3β phosphorylation and reactive oxygen species. One-month administration of 9S to triple transgenic AD (3 × Tg-AD) female mice (aged 6 months) led to significant improvement in cognitive deficits. Whereas similar treatment regimens for older 3 × Tg-AD female mice (aged 10 months) showed negligible neuroprotective effects. These findings suggest the importance of therapeutic intervention at the early stage of the disease.
研究领域:
神经科学
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药理学
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产品关联
DOI
PubMed
高影响因子
CHEMISTRY & BIODIVERSITY
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2024
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IF 2.3
Xingyuan Wang,Longjian Zhou,Yayue Liu,Fangfang Ban,Zhiyou Yang,Yongping Zhang,Xueqiong Hu,Yi Zhang
Screening Aβ aggregation inhibitors (AAIs) is important for Alzheimer's disease drug discovery. However, common cellular or biochemical methods are not suitable for high-throughput natural product screening. A gold nanoparticle (GNP) screening method was employed in this study to screen marine fungal crude extracts and pure compounds for quick AAI discovering. The anti-Aβ aggregation activity was further inspected using transmission electron microscopic (TEM) observation, and the interaction between active molecules and different Aβ species was revealed by molecular docking. The results indicated that the fungal extracts DLS2008001(M), BM3T2(M), DLEN2008005(M), TBG1-16(P), and TBG1-13(P) showed activity comparable to the positive control human serum albumin at the concentration of 500 µg/mL; 10 pure compounds also displayed moderate anti-aggregation activity, particularly nidulin, aspergillusidone G, and butyrolactone I. The inspection of anti-Aβ aggregation effect through TEM further demonstrated that extracts TBG1-16(P), DLS2008001(M), and BM3T2(M) dramatically inhibited the formation of Aβ aggregates. Molecular docking displayed low binding energies and key interactions of nidulin, aspergillusidone G, and butyrolactone I, with nine types of Aβ peptides. These findings indicate that the GNP method is efficient in screening AAIs and reveal marine fungal natural products as valuable sources of small molecular AAIs. Graphical GRAPHICAL
研究领域:
神经科学
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药理学
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生物技术
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分子生物学
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药物发现
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产品关联
DOI
PubMed
高影响因子
CHINESE JOURNAL OF CHEMISTRY
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2022
·Vol. 40
·期 15
·1821-1830
·
IF 5.56
Xin Lu,Yijun Liu,Nan Qin,Chenxi Du,Yanyu Hu,Yao Chen,Haopeng Sun
Comprehensive Summary The cholinesterases are essential targets implicated in the pathogenesis of Alzheimer's disease (AD). We have identified tryptophan-tetrahydroisoquinoline derivatives as selective micro-nanomolar butyrylcholinesterase (BChE) inhibitors. Molecular docking was applied for the rational design and binding mode analysis. They were defined according to their target inhibitory activity, low cytotoxicity, predicted permeability through the blood-brain barrier (BBB), and in vivo cognitive improvement. Additionally, the preferred compound showed ability to decrease self-induced Aβ 1-42 aggregation and Aβ 1-42 induced SH-SY5Y cell injury. Altogether, these factors indicated their potential as unique lead compounds for AD treatment.
研究领域:
神经科学
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药物化学
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分子生物学
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产品关联
DOI
高影响因子
Pharmaceutics
·
2025
·Vol. 17
·期 2
·177
·
IF 5.5
Jun Li,Dongqing Huang,Wanchen Liao,Yulin Wang,Yibiao Liu,Ping Luan
Background: The excessive accumulation of Aβ plays a critical role in the development of Alzheimer’s disease. However, the therapeutic potential of drugs like curcumin is often limited by low biocompatibility and BBB permeability. In this study, we developed a nanomaterial, BP-PEG-Tar@Cur, which was designed to enhance the biocompatibility of (curcumin) Cur, target Aβ, and augment BBB permeability through near-infrared (NIR) photothermal effects.Methods: Soluble Aβ, ThT fluorescence, and Aβ depolymerization fluorescence experiments were conducted to evaluate the ability of BP-PEG-Tar@Cur to inhibit Aβ aggregation and dissociate Aβ fibrils. Cell uptake assays were performed to confirm the targeting ability of BP-PEG-Tar@Cur towards Aβ. In vitro mitochondrial ROS clearance and in vivo detection of inflammatory factors were used to assess the anti-inflammatory and antioxidant properties of the nanodrug. Water maze behavioral experiments were conducted to evaluate the effect of BP-PEG-Tar@Cur on spatial memory, learning ability, and behavioral disorders in AD mice.Results: The nanodrug effectively inhibited Aβ aggregation and dissociated Aβ fibrils in vitro. BP-PEG-Tar@Cur demonstrated efficiency in curbing ROS overproduction in mitochondria and dampening the activation of microglia and astrocytes triggered by Aβ aggregation. Water maze behavioral experiments revealed that BP-PEG-Tar@Cur enhanced spatial memory, learning ability, and alleviated behavioral disorders in AD mice.Conclusions: Collectively, these findings demonstrate that BP-PEG-Tar@Cur has the potential to be an effective targeted drug for inhibiting Aβ aggregation and improving cognitive impairment in AD mice.
研究领域:
神经科学
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药理学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
Small
·
2024
·
IF 13
Qianhua Feng,Xueli Zhang,Xiaowen Zhao,Jia Liu,Qing Wang,Yuqi Yao,Huifang Xiao,Yucui Zhu,Wenwen Zhang,Lei Wang
The activated M1-like microglia induced neuroinflammation is the critical pathogenic event in Alzheimer's disease (AD). Microglial polarization from pro-inflammatory M1 toward anti-inflammatory M2 phenotype is a promising strategy. To efficiently accomplish this, amyloid-β (Aβ) aggregates as the culprit of M1 microglia activation should be uprooted. Interestingly, this study finds out that the self-reassembly of curcumin molecules into carrier-free curcumin nanoparticles (CNPs) exhibits multivalent binding with Aβ to achieve higher inhibitory effect on Aβ aggregation, compared to free curcumin with monovalent effect. Based on this, the CNPs loaded cardiolipin liposomes are developed for efficient microglial polarization. After intranasal administration, the liposomes decompose to release CNPs and cardiolipin in response to AD oxidative microenvironment. The CNPs inhibit Aβ aggregation and promote Aβ phagocytosis/clearance in microglia, removing roadblock to microglial polarization. Subsequently, CNPs are endocytosed by microglia and inhibit TLR4/NF-κB pathway for microglia polarization (M1→M2). Meanwhile, cardiolipin is identified as signaling molecule to normalize microglial dysfunction to prevent pro-inflammatory factors release. In AD transgenic mice, neuroinflammation, Aβ burden, and memory deficits are relieved after treatment. Through combined attack by extracellularly eradicating roadblock of Aβ aggregation and intracellularly inhibiting inflammation-related pathways, this nanotechnology assisted delivery system polarizes microglia efficiently, providing a reliable strategy in AD treatment.
研究领域:
神经科学
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药学
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产品关联
DOI
PubMed
高影响因子
ANALYST
·
2020
·Vol. 145
·期 20
·6579-6585
·
IF 3.978
Guanglei Lv,Yunze Xu,Jiajia Yang,Wenhui Li,Chunxia Li,Anyang Sun
Aberrant accumulation of Amyloid-β (Aβ) peptide is closely related to Alzheimer's disease. Thus, it is important to develop featured probes for the specific detection of Aβ species. Herein, we designed and synthesized a novel near-infrared fluorescent probe SDPY based on the D–π-A architecture for the detection of Aβ aggregates. The probe SDPY displayed higher affinity for Aβ40 aggregates over Aβ42 aggregates in solution (Kd = 164 nM vs. 2.1 μM). In addition, SDPY showed excellent anti-interference against a wide range of other substances. Furthermore, SDPY was capable of labeling Aβ40 aggregates better than Aβ42 aggregates in the brain sections of AD transgenic mouse models.
研究领域:
神经科学
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化学
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生物化学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ACS Chemical Neuroscience
·
2017
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IF 3.883
Jing Sun,Wenjie Xie,Xufeng Zhu,Mengmeng Xu,Jie Liu
Functionalized nanomaterials, which have been applied widely to inhibit amyloid-β protein (Aβ) aggregation, show enormous potential in the field of prevention and treatment of Alzheimer’s disease (AD). A significant body of data has demonstrated that the morphology and size of nanomaterials have remarkable effects on their biological behaviors. In this work, we proposed and designed three kinds of brain-targeting sulfur nanoparticles (RVG@Met@SNPs) with novel morphologies (volute-like, tadpole-like, and sphere-like) and investigated the effect of different RVG@Met@SNPs on Aβ–Cu2+ complex aggregation and their corresponding neurotoxicity. Among them, the sphere-like nanoparticles (RVG@Met@SS) exhibited the most effective inhibitory activity, due to their unique mini size effect, and they reduced 61.6% the Aβ–Cu2+ complex aggregation and increased 92.4% SH-SY5Y cell viability in a dose of 10 μg/mL. In vitro and in vivo, the abilities of different morphologies of RVG@Met@SNPs to cross the blood–brain barrier (BBB) and target brain parenchymal cells were significantly different. Moreover, improvements in learning disability and cognitive loss were shown in the transgenic AD mice model using the Morris water maze test after multiple doses of RVG@Met@SNPs treatment. In general, the purpose of this research is to develop a biological application of sulfur nanoparticles and to provide a novel functionalized nanomaterial to treat AD.
研究领域:
纳米技术
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神经科学
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药学科学
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材料科学
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产品关联
DOI
PubMed
高影响因子
ChemNanoMat
·
2019
·Vol. 5
·期 7
·897-910
·
IF 3.431
Yanan Liu,Jing Sun,Youcong Gong,Hui Zhou,Xu Chen,Xufeng Zhu,Yingyu Zhao,Yayu Wen,Xiuying Qin,Jie Liu
Graphical Peptide@POMs nanoparticles with Aβ-targeting peptides are used for Alzheimer's disease treatment in mice. First, synthetic peptide-modified Mo-POM nanoparticles are synthesized. Then, the assembled Peptide@POMs nanoparticles can effectively inhibit Zn 2+ -induced Aβ40 aggregation, penetrate the blood-brain barrier, and bind to Aβ. In addition, Peptide@POMs nanoparticles protect neurons from Aβ40-mediated neurotoxicity. The abnormal metabolism of amyloid-β (Aβ) peptide, as one of the main components of senile plaques, plays a vital role in the pathogenesis of Alzheimer's disease (AD). Our previous work showed that polyoxometalates (POMs) that inhibited the formation of Aβ aggregates were promising for AD therapy. Here, peptide-modified Mo polyoxometalate (Mo-POMs) nanoparticles were synthesized by the self-assembly of Aβ target peptide and Mo-POMs based on our previous work. Importantly, after modifying with the Aβ target peptide, the Mo polyoxometalate (Mo-POMs) nanoparticles exhibited enhanced blood-brain barrier (BBB) penetration and high binding affinity with Aβ species. The interactions between the Peptide@Mo-POMs nanoparticle and Aβ in the presence of Zn 2+ were comprehensively studied using physicochemical methods (spectroscopy, ThT fluorescence, turbidity tests). Peptide@Mo-POMs could suppress Aβ aggregation, disaggregate Aβ fibrils, and suppress Zn 2+ -induced Aβ aggregation. In addition, in vitro cell experiments revealed that Peptide@Mo-POMs could target and be well absorbed by PC12 cells, leading to the inhibition of intracellular Aβ aggregation and reduced Aβ aggregates-induced cytotoxicity. The blood-brain barrier (BBB) permeability of Peptide@Mo-POMs was also revealed by the Transwell experiment. This study gives a mechanistic understanding into how Peptide@Mo-POMs can work through a synergistic interaction with metal ions and Aβ, and provides new insights into the design and synthesis of POMs as Aβ inhibitors in the treatment of AD.
研究领域:
纳米医学
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神经科学
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材料科学
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生物化学
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）