Cell Reports Physical Science
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2023
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IF 8.9
Zhu Chang,Bicheng Zhu,Jinjin Liu,Hui Dong,Yuanqiang Hao,Yanli Zhou,Jadranka Travas-Sejdic,Maotian Xu
Summary β-Secretase, the β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1), is a key hydrolytic enzyme in the pathway of β-amyloid (Aβ) production in the brain of a patient with Alzheimer’s disease (AD). BACE1 is considered a promising biomarker for the early detection of AD. A ferrocene probe (Fc-Probe) is synthesized, where the aldehyde group on the probe can specifically recognize the N terminus of the APP peptide fragment. The sensor’s design involves gold nanoparticles (AuNPs) on a glassy carbon electrode (GCE) surface, which allows for the binding of the APP peptide fragment. When BACE1 cleaves the acetylated APP peptide, the N terminus is exposed and triggers an electrochemical signal from the Fc-Probe. The developed sensor can detect BACE1 in a range of 0.02 to 50 U/mL, with a detection limit of 8.0 mU/mL. Such a BACE1 sensor provides a simple, sensitive, and low-cost detection methodology, enabling the “signal-on” detection of BACE1 activity.
研究领域:
生物化学
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神经科学
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分析化学
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诊断学
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DOI
高影响因子
CHEMISTRY-A EUROPEAN JOURNAL
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2023
·Vol. 29
·期 28
·e202300450
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IF 4.3
Yanli Zhou,Zihan Huang,Jiaxiang Liu,Hui Dong,Yintang Zhang,Maotian Xu,Yanfeng Bi
Graphical An electrochemical assay for probing the cleavage of surface-confined APP peptide substrates by BACE1 was developed based on specific chemical labeling of terminal tyrosine. Beta-site secretase (BACE1) catalyzes the cleavage of amyloid precursor protein (APP), which process ultimately lead to plaque deposition in the brain of Alzheimer's disease (AD). Thus, accurate monitor of BACE1 activity is essential to screen inhibitors for AD treatment. This study develops a sensitive electrochemical assay for probing BACE1 activity based on silver nanoparticles (AgNPs) and tyrosine conjugation as tags and a marking method, respectively. An APP segment is firstly immobilized on aminated microplate reactor. Cytosine (C) rich sequence-templated AgNPs/Zr-based metal–organic framework (MOF) composite is modified by phenol groups, and then the prepared tag (ph-AgNPs@MOF) is captured in microplate surface by the conjugation reaction of phenolic groups between tyrosine and tag. After cleavage by BACE1, the solution containing ph-AgNPs@MOF tags is transferred to the screen-printed graphene electrode (SPGE) surface for voltammetric detection of AgNP signal. This sensitive detection for BACE1 provided an excellent linear relationship between 1 to 200 pM with a detection limit of 0.8 pM. Furthermore, this electrochemical assay is successfully applied for screening of BACE1 inhibitors. This strategy is also verified to be used for evaluation of BACE1 in serum samples.
研究领域:
生物化学
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分析化学
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神经科学
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纳米技术
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DOI
PubMed
高影响因子
CERAMICS INTERNATIONAL
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2022
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IF 5.532
Jiayao Lu,Ying Li,Wenlong Huang
In this study, BaCe 1− x La x O 3− δ ( x = 0.05, 0.10, 0.20, and 0.30) oxides synthesized using citrate–nitrate combustion method were calcined at 1100 °C for 5 h and subsequently sintered at 1550 °C for 5 h. Crystal structure, conductivity, and chemical properties were investigated via X-ray diffraction (XRD), alternating current (AC) impedance spectroscopy , and X-ray photoelectron spectroscopy (XPS). XRD analysis shows that all samples have orthorhombic perovskite-type structure, and lattice volume increases with increasing La content. XPS results show that Ba and La valence states are bivalent, and trivalent, respectively. Mixed Ce 4+ and Ce 3+ valence states can be identified in the samples. Furthermore, there are two types of O binding states in perovskite structure: (i) O–H groups/oxygen vacancies and (ii) lattice oxygen. AC impedance spectra reveal that all samples are proton–oxide ion–electron hole conductors at 400–800 °C in wet O 2 atmosphere and proton–electron conductors at 400–800 °C in wet Ar atmosphere. Among these samples, BaCe 0.90 La 0.10 O 3− δ and BaCe 0.95 La 0.05 O 3− δ display the highest conductivities at temperatures below and above 500 °C, respectively. Furthermore, BaCe 0.95 La 0.05 O 3− δ exhibits the highest total conductivity of 1.06 × 10 −2 S cm −1 at 800 °C under P O2 ≈ 1 atm and P H2O = 0.006 atm.
研究领域:
材料科学
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电化学
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DOI
高影响因子
Translational Neurodegeneration
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2025
·Vol. 14
·期 1
·1-20
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IF 15.2
Li Zhaohan,Yang Jun,Li Jianan,Zhao Shuxuan,Jiang Shaoping,Liu Weimin,Li Xinjian,Zhang Simeng,Du Haiyan,Ni Junjun,Huang Yuanyu,Qing Hong,Ruan Shaobo
Background The deposition of toxic aggregated amyloid-β (Aβ), resulting from continuous cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase, is a key pathogenic event in Alzheimer's disease (AD). Small interfering RNAs (siRNA) have shown great potential for disease treatment by specifically silencing target genes. However, the poor brain delivery efficiency of siRNAs limits their therapeutic efficacy against AD. Methods We designed a simplified and effective BACE1 siRNA (siBACE1) delivery system, namely, dendritic polyamidoamine modified with the neurotropic virus-derived peptide RVG29 and polyethylene glycol (PPR@siBACE1). Results PPR@siBACE1 crossed the blood–brain barrier efficiently and entered brain parenchyma in large amount, with subsequent neurotropism and potential microglia-targeting ability. Both in vitro and in vivo studies validated the effective brain delivery of siBACE1 and strong BACE1 silencing efficiency. Treatment of AD mice with PPR@siBACE1 inhibited the production of Aβ, potentiated Aβ phagocytosis by microglia, improved the memory deficits and reduced neuroinflammatory response in AD mice. Conclusions This study provides a reliable delivery platform for gene therapies for AD.
研究领域:
神经科学
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分子生物学
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药剂学
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基因治疗
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DOI
PubMed
高影响因子
ANALYTICAL AND BIOANALYTICAL CHEMISTRY
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2023
·Vol. 415
·期 12
·2209-2215
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IF 4.3
Dai Tiantian,Qiu Mingyue,Li Hongyu,Yang Mingyan,Gao Jie,Li Xinmin,Lv Jiajia,Yang Minghui,Yuan Zeli,Luo Junjun
In this work, a simple and sensitive electrochemical sensor was proposed for the detection of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) activity. Firstly, the BACE1 specific peptide was modified onto the Au electrode to graft a single-strand DNA with polycytosine DNA sequence (dC 12 ) via amide bonding between peptide and dC 12 . Because the dC 12 is abundant in phosphate groups, thus it can react with molybdate to form redox molybdophosphate, which can generate electrochemical current. Using BACE1 as a model peptidase, the proposed sensor shows a linear response range from 1 to 15 U/mL and limit of detection down to 0.05 U/mL. The sensor displays good performance for the BACE1 activity detection in human serum samples, which may have potential applications in the clinical diagnostics of Alzheimer’s disease. Graphical Abstract
研究领域:
生物化学
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医学诊断
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神经科学
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DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY
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2022
·Vol. 37
·期 8
·1902-1913
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IF 4.109
Ruike Wang,Zuntao Wu,Rundong Liu,Lin Bai,Yan Lin,Yue Ba,Hui Huang
Numbers of emerging evidence suggest that lead (Pb) exposure contributes to cognitive decline and might also increase the risk of Alzheimer's disease (AD) dementia in the elderly by increasing the beta-amyloid burden. Here, we aimed to characterize the effects of Pb on the post-transcriptional regulators, microRNAs (miRNAs), which may participate in AD pathogenesis. At first, early chronic Pb exposure on neuronal miRNAs expression with increasing aging was profiled to elucidate the association of three selected miRNAs with β-site APP-cleaving enzyme 1(BACE1), a rate-limiting enzyme for β-amyloid (Aβ) production. Next, we verified changes in BACE1 were observed by regulating miRNAs expression in vitro. While Pb promoted BACE1 levels, BACE1 levels were reduced in SH-SY5Y cells with miR-124-3p mimic, suggesting for the first time that miR-124-3p/BACE1 pathway modulation is critically involved in Pb-induced AD-like amyloidogenic processing. Findings from this study could provide new insight into the molecular mechanisms of Pb-associated neurodegenerative pathogenesis from an epigenetic perspective.
研究领域:
神经科学
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分子生物学
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毒理学
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表观遗传学
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DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
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2016
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IF 5.886
Fengli Qu,Minghui Yang,Avraham Rasooly
The protease BACE1 (the β-site amyloid precursor protein cleaving enzyme 1) catalyzes the first step in the synthesis of β-amyloids (Aβ), peptides that accumulate in the brain in Alzheimer’s disease (AD). Measurement of BACE1 activity is important for the development of BACE1 inhibitors to slow or stop AD. To measure BACE1 cleavage of the electrode-immobilized substrate peptide, we developed a redox-generating hydroxyapatite (HAP) probe which generates electrochemical current by reaction of the nanoparticle with molybdate (MoO42–). The probe combines alkaline phosphatase (ALP) for dual signal amplification and Aβ antibody to bind the probe to the immobilized peptide substrate on the surface of the electrode. We measured the activity of BACE1 at concentrations ranging from 0.25 to 100 U/mL. The use of the dual-signal HAP–ALP probe increased the signal by an order of magnitude compared to HAP-only probe, enabling detection limits as low as 0.1 U/mL. To measure the inhibition of BACE1 activity, the BACE1 inhibitor OM99-2 was added to 25 U/mL of BACE1 in concentrations ranging from 5 to 150 nM. The observed detection limit of inhibition is 10 nM of OM99-2. These results demonstrate the capabilities of this novel biosensor to measure BACE1 activity and inhibitors of BACE1 activity. To the best of our knowledge this is the first report that reaction of HAP nanoparticles with molybdate can generate electrochemical current. This dual signal amplification strategy can be extended to other electrochemical assays and adapted for wide applications.
研究领域:
生物化学
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医学诊断
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神经科学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF HYDROGEN ENERGY
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2025
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IF 8.3
Zhiyong Yang,Guofang Zhang,Ruiqin Zhang,Lu Bai,Jianyi Xu,Ping Yuan,Lingliang Kong,Jingyi Zhang,Juan Du
The development of nickel-metal hydride battery anodes has long been limited by the inherent capacity decay of the anodes of the metal alloy materials. In this study, the BaCe 1-x Li x O 3 solid solutions with controlled contents of Li + ions (x = 0–0.8) were synthesized via combustion method and adopted them as the novel negative materials to offer a breakthrough in overcoming traditional performance constraints. The influences of Li + contents on microstructure and electrochemical hydrogen storage performance were systematically investigated. X-ray Diffraction test (XRD) confirmed that the Li + ions were successfully incorporated into the BaCeO 3 lattice and substituted at the Ce 4+ sites. The grain sizes were gradually decreased from 73.5 nm (undoped) to 67.0 nm (Li 0.08 ). Scanning Electron Microscope (SEM) and Transmission Electron Microscope (TEM) results further supported the reduction of the grain sizes and proved that the Li + ions had doped into the lattice of the BaCeO 3 . Spectral tests showed that the Li + ions induced obvious changes in the lattice structures and the concentration of oxygen vacancies. Electrochemical hydrogen storage performance tests demonstrated that the discharge capacity of BaCe 0.96 Li 0.04 O 3 achieved 212.7 mAh/g, representing 95.1 % improvement over the undoped sample (109.0 mAh/g), along with higher charge retention. Kinetic analysis further confirmed the superior hydrogen storage kinetic behavior of the doped samples. These results fully proved that the doping of Li + ions can effectively enhance the hydrogen storage performances of BaCeO 3 materials.
研究领域:
材料科学
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电化学
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储能技术
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固体化学
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DOI
高影响因子
Science China-Chemistry
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2025
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IF 9.7
Jiang Yifan,Li Lisha,Fang Xiao,Zeng Tao,Su Lichao,Liu Yichang,Wu Ying,Li Jinyu,Lyu Peng,Lu Zhonglei,Lu Chunhua,Yang Huanghao
The development of RNA interference (RNAi) therapy offers a potential solution for Alzheimer’s disease (AD). However, the brain-blood barrier (BBB) with its selective permeability and pharmacokinetic-related challenges poses restrictions on the delivery of small interfering RNA (siRNA) to the central nervous system (CNS). In this study, we demonstrate that the incorporation of 2′-fluoro (2′-F) substitutions and L-carnitine modification facilitates the self-assembly of siRNA through triple interaction, leading to the formation of nanorings, called LCSF-NR. Based on the enhanced cellular uptake and lysosomal escape by 2′-F substitution and the transport across the BBB promoted by L-carnitine, the nanorings realized the improved brain-targeted delivery of siRNA, both in zebrafish and mice models. Moreover, our findings highlight the therapeutic potential of LCSF-NR formulation in an AD zebrafish model through a synergistic effect of downregulating the β-site APP cleavage enzyme 1 (BACE1) gene and L-carnitine-mediated neuroprotection, effectively inhibiting pathological processes. Overall, these results suggest that the chemical modification-based siRNA self-assembly strategy enables trans-BBB delivery and presents a concise approach for synergistic therapy of AD.
研究领域:
分子生物学
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神经科学
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药物递送系统
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产品关联
DOI
高影响因子
Acta Pharmaceutica Sinica B
·
2025
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IF 14.6
Yanyan Xu,Xiangtong Ye,Yanfeng Du,Wenqin Yang,Fan Tong,Wei Li,Qianqian Huang,Yongke Chen,Hanmei Li,Huile Gao,Weiwei Zhang
Alzheimer’s disease (AD), characterized by β -amyloid (A β ) aggregation and neuroinflammation, remains a formidable clinical challenge. Herein, we present an innovative nose-to-brain delivery platform utilizing lactoferrin (Lf)-functionalized lipid nanoparticles (LNPs) co-encapsulating α -mangostin ( α -M) and β -site APP cleaving enzyme 1 (BACE1) siRNA (siB). This dual-modal therapeutic system synergistically combines the neuroprotective and microglia-reprogramming capabilities of α -M with the transcriptional silencing of BACE1 via siB, thereby simultaneously inhibiting A β production and enhancing its clearance. Fabricated via a microfluidic approach, the LNPs exhibited uniform particle size distribution, great encapsulation efficiency, and robust colloidal stability. Upon intranasal administration, Lf-functionalization enabled superior brain-targeting efficacy through receptor-mediated transcytosis. In vitro studies demonstrated that α -M reversed A β -induced low-density lipoprotein receptor downregulation, promoting microglial phagocytosis and autophagic degradation of A β , while siB effectively suppressed BACE1 expression, abrogating A β synthesis. In vivo investigations in APP/PS1 transgenic mice revealed remarkable cognitive recovery, substantial A β plaque reduction, and alleviation of neuroinflammation and oxidative stress. This intricately designed LNP system, exploiting a non-invasive and efficient nose-to-brain delivery route, provides a biocompatible, synergistic, and transformative therapeutic strategy for the multifaceted management of AD.
研究领域:
神经科学
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药剂学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
FITOTERAPIA
·
2023
·
IF 3.4
Saijuan Li,Fangge Wu,Pengcheng Gao,Can Jin,Yuyong Wang,Wenfeng Liao,Kan Ding
The accumulation of amyloid β (Aβ) containing senile plaques is one of the key histopathological hallmarks of Alzheimer's disease (AD). Increasing evidences demonstrated the important role of autophagy in Aβ clearance. Recent studies implied that extracts from Semiaquilegia adoxoides (DC.) Makino could ameliorate the memory of D-galactose induced aging mice. However, the bioactive substance and underlying mechanism remains unknown. Thus, the present study sought to explore the effects of a novel homogenous peptidoglycane on Aβ 42 secretion and the underlying mechanism. Briefly, we extracted a novel peptidoglycan named SA02C using hot water extraction and alcohol precipitation with the Mw of 13.72 kDa. SA02C contains 73.33% carbohydrate and 27.83% protein. The structure characterization revealed that its glycan part might mainly composed of galacturonic acid with minor rhamnose in backbone, and branched with glucose, galactose, arabinose, xylose and galacturonic acid. The protein or peptide moiety in SA02C was bonded to the polysaccharide via threonine. Bioactivities test showed that SA02C could reduce Aβ 42 production in a dose dependent manner with no obvious cytotoxicity. Mechanism study demonstrated that SA02C could modulate APP processing by upregulating the expression of ADAM10, sAPPα and downregulating BACE1, sAPPβ. Furthermore, SA02C also could stimulate autophagy by promoting the expression of the markers of autophagy such as LC3B and ATG5, resulting in the promotion of Aβ 42 phagocytosis.
研究领域:
药理学
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神经科学
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分子生物学
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植物化学
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产品关联
DOI
PubMed
高影响因子
NEUROCHEMISTRY INTERNATIONAL
·
2021
·
IF 3.921
Ying Xu,Yunxia Dong,Cong Wang,Qian Jiang,Haichao Chu,Yue Tian
As a general anesthetic widely used in surgical, sevoflurane has been shown to cause cognitive and memory deficits in the elderly. It's important to find out agents that can counteract sevoflurane-induced cognitive dysfunction. This study is aimed to investigate the effect of lovastatin on sevoflurane-induced cognitive impairment in aged rats and reveal the potential mechanisms. BV-2 cells, rat hippocampal neurons or male aged rats were exposed to 2% sevoflurane for 5 h. The cells were pretreated with 10 μM lovastatin. The rats were intraperitoneally injected with 5 mg/kg/day lovastatin for three days. The results showed that lovastatin enhanced exosomal IDE secretion from sevoflurane-exposed BV-2 cells and promoted Aβ degradation. Lovastatin treatment also inhibited the increased expressions of β-secretase 1 (BACE1) and γ-secretase in hippocampal neurons under sevoflurane exposure in vitro . In animal experiments, the discrimination index in novel object recognition test and percentage of spontaneous alternation in Y-maze test were significantly elevated after lovastatin administration. In addition, Aβ plaque area and contents of soluble Aβ 1-40 and Aβ 1-42 in the hippocampal tissues were decreased upon lovastatin treatment. Furthermore, lovastatin reversed sevoflurane-induced Aβ accumulation via up-regulating IDE expression, and down-regulating amyloid precursor protein (APP)-related protein expression (β-C-terminal fragment (CTF), BACE1 and γ-secretase). In conclusion, lovastatin alleviates sevoflurane-induced cognitive deficient in aged rats via promoting Aβ degradation and reducing Aβ production. Lovastatin may be beneficial in preventing anesthetic-induced cognitive impairment.
研究领域:
神经科学
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药理学
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麻醉学
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老年医学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）