MICROCHEMICAL JOURNAL
·
2024
·
IF 4.9
Chencheng Luo,Tianyi Yang,Yizhi Zhang,Lei Wu,Xiaoyu Zhu,Zhiyu Qian
Accurate detection of Alzheimer’s disease (AD) core biomarkers in body fluid is critical for identifying latent asymptomatic AD patients and prediction AD progress. Amyloid beta 1–40 (Aβ-40) as one of the core biomarkers, is expected to be an early diagnostic indicator for AD. Here, we establish a competitive method based on hairpin-structured aptamer for rapid and highly sensitive detection of Aβ-40 using square wave voltammetry (SWV). A hairpin aptamer with redox-active moiety methylene blue (MB) are immobilized on a gold working electrode as a recognition element. In the detection, a short complementary oligonucleotide strand is first introduced to switch on the hairpin, whereafter the targets Aβ-40 join in and selectively react with the aptamer in a competitive manner with the complementary strand, leading to the changes in the proximity of MB to the electrode and thereby in the electrochemical signal. Various parameters such as aptamer concentration, complementary chain length, incubation time, and temperature were optimized to achieve maximum sensing performance. By introducing a complementary chain, the sensor significantly reduces the detection limit to 7.14 pg/mL, with a dynamic range of 20 pg/mL to 200 ng/mL. Additionally, high selectivity of the sensor for Aβ-40 monomer (Aβ-40 m) over other forms of Aβ peptides has been validated. The hairpin-mediated detection method enables rapid, facile and highly sensitive detection of Aβ-40 using low-cost screen-printed electrode (SPE) platform, providing a wide range of possibilities for the early diagnosis of AD in point-of-care technologies (POCT).
研究领域:
生物医学
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分析化学
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DOI
高影响因子
Advanced Science
·
2026
·
IF 14.1
Jie Miao,Jing Wang,Yankun Li,Haipei Zhang,Yanli Zhang,Qingnian Li,Bo Xiao,Wenhu Zhou,Junhong Guo
Alzheimer's disease (AD) is characterized by amyloid‐β (Aβ) accumulation, neuroinflammation, and vascular dysfunction, yet effective therapies remain limited. Impaired Aβ clearance across the blood–brain barrier (BBB) is a key contributor to AD pathogenesis. Two sequential barriers to Aβ clearance are identified: proprotein convertase subtilisin/kexin type 9 (PCSK9) upregulation in cerebrovascular endothelial cells compromises low‐density lipoprotein receptor‐related protein 1 (LRP1)‐mediated Aβ efflux, whereas increased intracellular Aβ handling after PCSK9 silencing induces tribbles pseudokinase 3 (TRIB3) upregulation and exposes an autophagy blockade restricting intracellular Aβ degradation. PCSK9 silencing restores LRP1 expression and enhances Aβ uptake and efflux, whereas TRIB3 knockdown restores autophagic flux and facilitates Aβ degradation. SITR (siPCSK9/siTRIB3@TPN‐RAP), a RAP‐modified siRNA nanodelivery system based on tea polyphenol nanoparticles (TPNs), enables brain‐enriched co‐delivery of siPCSK9 and siTRIB3. SITR enhances BBB penetration and preferentially accumulates in cerebrovascular endothelial cells and microglia. In APP/PS1 mice, SITR improves cognitive performance, reduces Aβ and cerebral amyloid angiopathy burden, preserves vascular and neuronal homeostasis, and suppresses neuroinflammation, while showing no overt short‐term systemic toxicity under a 6‐week regimen. These findings establish PCSK9 and TRIB3 as complementary therapeutic targets and support SITR as an effective nanoplatform integrating enhanced Aβ efflux with restored autophagic degradation for AD intervention. PCSK9 upregulation in cerebrovascular endothelial cells and microglia destabilizes the Aβ transporter LRP1, while TRIB3‐associated autophagy blockade further limits intracellular Aβ degradation. A RAP‐modified tea‐polyphenol nanoparticle co‐delivers siPCSK9 and siTRIB3 to restore LRP1‐mediated Aβ efflux and autophagy‐dependent degradation, reducing Aβ deposition, cerebral amyloid angiopathy, BBB disruption, and neuroinflammation in APP/PS1 mice.
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PubMed
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
·
2019
·
IF 5.657
Hong Huang,Xiaobing Lou,Bingwen Hu,Zhongneng Zhou,Jinquan Chen,Yang Tian
In the amyloid plaques , a signature of AD, abnormally high Cu 2+ concentrations are found bound to Aβ. Most of previous studies reported that Cu-Aβ could contribute to oxidative stress , as H 2 O 2 and •OH are catalytically generated by Cu-Aβ with the assistance of biological reductant, with only one recent report stated that free O 2 •- is also generated in the Cu-Aβ catalyzed processes, where an indirect technique was applied. To comprehensively investigate the free radicals produced during this Cu-Aβ-mediated process with a biological reductant, DNA-cleavage assay, an indirect method, and two direct methods including electron paramagnetic resonance (EPR) spectroscopy and transient absorption spectroscopy (TAS), both having qualitative and quantitative power, were employed in this work. All the experimental results obtained from the three methods demonstrated that Cu-Aβ in the biological reducing environment was not only able to catalyze the production of H 2 O 2 and •OH, but also to generate free O 2 •- . The results further indicated that O 2 •- was the precursor of H 2 O 2 and •OH. It is also important to note that the results obtained from EPR spectroscopy and TAS provided direct evidence for the presence of O 2 •- and •OH. By virtue of the direct techniques, we also found that the longest peptide fragments of Aβ 16 , Aβ 40 , and Aβ 42 produced the least radicals with a lowest rate. More interestingly, the fibrillar forms of Aβ generated less O 2 •- and •OH compared with oligomeric and monomeric forms.
研究领域:
神经生物学
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医学
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生物化学
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DOI
PubMed
高影响因子
Scientific Reports
·
2025
·Vol. 15
·期 1
·40440
·
IF 3.9
Jin Chen,Ma Zhihao,Wu Peipei,Qian Hui,Su Lin,Zhu Zhiqiang,Wang Jie
Alzheimer’s disease is an increasingly prevalent neurodegenerative disorder characterized by the accumulation of misfolded Aβ aggregates. The efficacy of upconversion nanomaterials in photodynamic therapy has been proven, yet their applicability is constrained by their inherent toxicity. In this study, exosomes derived from stem cells, combined with targeting molecules, were utilized to encapsulate upconversion nanoparticles for targeted removal of pathogenic amyloid aggregates in Alzheimer’s disease. Evidence from AFM and TEM imaging, fluorescence spectroscopy, and cell-based experiments demonstrates that the clearance efficiency of amyloid aggregates is enhanced, and the cytotoxicity induced by misfolded Aβ aggregates is significantly reduced in nerve cells. Notably, the viability of neural PC12 cells is partially restored even in the presence of toxic amyloid aggregates.
研究领域:
神经科学
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纳米技术
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生物医学工程
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分子医学
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阿尔茨海默病研究
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DOI
PubMed
高影响因子
Science China-Chemistry
·
2021
·Vol. 65
·期 2
·339-352
·
IF 9.445
Wang Yipu,Mei Dong,Zhang Xinyi,Qu Da-Hui,Mei Ju
Precise and early detection of β -amyloid (A β ) deposits in situ and in real time is pivotal to the diagnosis and early intervention of Alzheimer’s disease (AD). Optical imaging stands out to be a promising technique for such a task; however, it still remains a big challenge, due to the lack of high-performance imaging contrast agent. Restricted by poor blood-brain barrier (BBB) penetrability, short-wavelength excitation and emission, as well as the aggregation-caused quenching effect, the widely used gold-standard probes cannot be used for early in-vivo imaging of A β deposits. Herein, we integrate the A β deposits-favored geometry, amphiphilic and zwitterionic molecular structure, extended D-π-A electronic structure, and 3D conformation into one molecule, facilely establishing a simple and economic imaging contrast agent that enjoys high specificity and affinity to A β deposits, good BBB penetrability, bright red/near-infrared fluorescence, low interference from autofluorescence, aggregation-induced emission (AIE) feature, high signal-to-noise ratio (SNR), and high contrast. In-vitro, ex-vivo , and in-vivo experiments with different strains of mice indicate that AIE-CNPy-AD holds the universality to A β deposits identification. Noteworthily, AIE-CNPy-AD is even able to precisely trace the small and sparsely-distributed A β deposits in AD model mice as young as 4-month-old APP/PS1 mice, the youngest having A β deposits. Moreover, the present probe could clearly reveal the increase and enlargement of A β deposits as the mice grow. Therefore, AIE-CNPy-AD might be an ideal alternative for early AD diagnosis and highly reliable monitoring of AD progression.
研究领域:
神经生物学
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医学影像学
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分子探针设计
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DOI
高影响因子
ELECTROANALYSIS
·
2026
·Vol. 38
·期 1
·e70098
·
IF 2.3
Qiu Jin,Xuyuan Chen,Xiaoying Wang
Excessive oligomeric Amyloid- β (A β Os) in the brain induces strong neurotoxicity and are a major causative marker of Alzheimer's disease (AD). Herein, an exemplary electrochemiluminescence (ECL) aptasensor for A β Os that coupled a triple-helix switchable system (THSS) with gold-doped Ru(bpy) 3 2+ /copper luminescent-nanospheres (RuCu@AuLNs) was successfully developed. In brief, the anti-A β Os aptamer (Apt) with two symmetric arms and RuCu@AuLN-marked signal transduction DNA (RuCu@AuLNs-ST) perfectly constructed the THSS on a gold electrode surface via hybridization reaction. At this point, the THSS was closed, and a strong initial ECL signal ( I ECL0 ) output was generated. Once A β Os appeared, they specifically bound with Apt and opened the THSS, releasing RuCu@AuLNs-ST from electrode surface, and degressive ECL signal ( I ECL1 ) was obtained. Thus, the aptasensor detected A β Os-dependent I ECL1 change (Δ I ECL1 = I ECL0 − I ECL1 ) with a concentration range of 1 fM to 1 pM with a low detection limit of 0.5 fM, and demonstrated good reliability and practicality in human serum. Additionally, the reconfigurability of the sensor allows it to be continuously reused up to 5 times at a concentration of 1 fM A β Os. The developed ECL aptasensor could be used as a cost-effective tool for early diagnosis of AD. Moreover, the strategy has promising application in the bioassays of various analytes.
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高影响因子
SENSORS AND ACTUATORS B-CHEMICAL
·
2026
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IF 8.3
Fei Gao,Wanquan Lin,Xiaorong Jiao,Yanxia Zhang,Tingting Zhao,Jinlong Zhang,Dong Pei,Duolong Di,Lichao Yang,Jun Hai
Cascade nanoprobe converts lysosomal cholesterol into dual-mode optical signals • Au-Cu core enables cascade-compatible amplification with cellular operability • Probe visualizes A β /OA-associated lysosomal cholesterol dysregulation in cells • In vivo imaging and MALDI-MSI support brain cholesterol-associated activation Alzheimer’s disease (AD) has been linked to aberrant cholesterol handling in the endolysosomal system, but there are still few analytical tools that show cholesterol dysregulation in living cells and relate it to A β -associated autophagy-related stress responses. Here, we created HBC@Au-Cu, a cascade nanoplatform that targets lysosomes. Within a single nanostructure, this system spatially combines dual-mode optical signaling, Au-Cu catalytic amplification, H 2 O 2 relay, and cholesterol oxidation. We defined catalyst selection at the cascade level instead of choosing the catalytic component only on the basis of peroxidase-like activity. The Au-Cu bimetallic core was chosen after taking into account cytocompatibility, fluorescence transduction compatibility, and catalytic amplification. Cholesterol was transformed into complementary colorimetric and fluorescence outputs within the integrated cascade system, providing linear response ranges of 0–100 μM (R 2 = 0.9955) and 0–10 μM (R 2 = 0.9972), respectively. HBC@Au-Cu increased lysosomal fluorescence in an A β /OA-induced AD-like cellular model, which was reduced by cholesterol-modulating treatments in the same pathological setting. The probe produced increased head-region and ex vivo brain fluorescence in 5xFAD mice, and MALDI-MSI also showed a spatial correlation between probe activation and the endogenous cholesterol ion signal (r = 0.88). All of these findings point to HBC@Au-Cu as a chemical platform that converts cholesterol dysregulation into a quantifiable intracellular phenotype accompanied by p62/LC3-associated autophagy-related stress responses. They also demonstrate the analytical potential of cholesterol-responsive imaging in AD-related models and provide a basis for its future evaluation in early-stage AD assessment. Download: Download high-res image (274KB) Download: Download full-size image
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高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2021
·
IF 6.291
Lin Bai,Rundong Liu,Ruike Wang,Yongjuan Xin,Zuntao Wu,Yue Ba,Huizhen Zhang,Xuemin Cheng,Guoyu Zhou,Hui Huang
This study examined the neuroprotective properties of resveratrol (Res) and its target sirtuin1 (SIRT1) against lead (Pb)-mediated toxicity and discovered that both resveratrol treatment and SIRT1 overexpression restored blocked autophagic flux as well as reduced β-amyloid (Aβ) contents. Four-week-old male C57BL/6 mice were employed to consumed 0.2% Pb(Ac) 2 solution or deionized water for 3 months followed by 12 months of Res (50 mg/kg BW) or vehicle gavage. In in vitro study, SH-SY5Y cells were pretreated with the SIRT1 activator SRT1720 (2 μM) or the inhibitor EX527 (2 μM) for 2 h, then 25 μM of Pb(Ac) 2 was added and incubated for 48 h. Western blotting, RT-qPCR, enzyme-linked immunosorbent assay (ELISA), and Lyso-Tracker Red Staining were next used to estimate the potential alterations of the autophagic pathway as well as BACE1-mediated amyloid processing in response to Pb exposure, respectively. Our data revealed that Res treatment or SIRT1 activation resisted the induction of autophagy by Pb exposure through inhibition of LC3 and Beclin-1 expression and promoted the degradation of Aβ and Tau phosphorylation. Besides, the SIRT1 activator (SRT1720) downregulated the expression of BACE1, the rate-limiting enzyme for Aβ production, by inhibiting the activation of nuclear factor-κB (NF-κB) in Pb-treated SH-SY5Y cells, which resulted in reduced Aβ production. Collectively, we verified the role of Res-SIRT1-autophagy as well as the SIRT1-NF-κB-BACE1 pathway in Pb-induced neuronal cell injury by in vivo or in vitro models. Our findings further elucidate the important role of SIRT1 and Res in counteracting Pb neurotoxicity, which may provide new interventions and targets for the subsequent treatment of neurodegenerative diseases.
研究领域:
神经科学
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药理学
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毒理学
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PubMed
高影响因子
Asian Journal of Pharmaceutical Sciences
·
2024
·
IF 10.7
Kang Qian,Peng Yang,Yixian Li,Ran Meng,Yunlong Cheng,Lingling Zhou,Jing Wu,Shuting Xu,Xiaoyan Bao,Qian Guo,Pengzhen Wang,Minjun Xu,Dongyu Sheng,Qizhi Zhang
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-14G 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 Aβ affinity greatly inhibited Aβ oligomerization/fibrillation, and interrupted Aβ interaction with neuron/microglia by reducing neuronal mitochondrial Aβ deposition and promoting microglial phagocytosis of Aβ. 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.
研究领域:
神经科学
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药理学
·
生物技术
·
分子生物学
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DOI
PubMed
高影响因子
Communications Chemistry
·
2025
·Vol. 8
·期 1
·1-12
·
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
·
神经科学
·
生物物理学
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DOI
PubMed
高影响因子
ANALYTICAL AND BIOANALYTICAL CHEMISTRY
·
2024
·
IF 3.8
Wei Yuxin,Bai Qingqing,Ning Xinlu,Bai Xiaofan,Lv Jie,Li Meng
Sensitive and accurate detection of the amyloid-β (Aβ) monomer is of fundamental significance for early diagnosis of Alzheimer’s disease (AD). Herein, inspired by the specific Cu-Aβ monomer coordination, a cutting-edge colorimetric assay based on single-atom Cu anchored N-doped carbon nanospheres (Cu-NCNSs) was developed for Aβ monomer detection and an amyloidogenesis study. By directly pyrolyzing Cu 2+ -incorporated covalent organic frameworks (COFs), the resulting Cu-NCNSs with a high loading of Cu (8.04 wt %) exhibited outstanding peroxidase-like activity. The strong binding affinity of Aβ monomer to Cu-NCNSs effectively inhibited their catalytic activity, providing the basis for the colorimetric assay. The Cu-NCNSs-based sensor showed a detection limit of 1.182 nM for Aβ monomer, surpassing traditional techniques in terms of efficiency, accuracy and simplicity. Moreover, the system was successfully utilized for Aβ monomer detection in rat cerebrospinal fluid (CSF). Notably, the distinct inhibitory effects of monomeric and aggregated Aβ species on the catalytic activity of Cu-NCNSs were allowed for monitoring of the dynamic aggregation process of Aβ. Compared to thioflavin T (ThT), the most widely used amyloid dye, the detection system exhibited greater sensitivity towards toxic Aβ oligomers, which was crucial for early AD diagnosis and treatment. Our work not only sheds light on the rational design of highly active single-atom nanozymes from COFs but also expands the potential applications of nanozymes in early disease diagnosis. Graphical
研究领域:
生物化学
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医学诊断
·
纳米材料科学
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产品关联
DOI
PubMed
高影响因子
LANGMUIR
·
2020
·
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
·
纳米材料科学
·
神经退行性疾病研究
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）