Journal of Materials Chemistry B
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2022
·Vol. 11
·期 7
·1445-1455
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IF 7.571
Yijia Guan,Weijie Cao,Tao Li,Jieyi Qin,Qilong He,Xiaofeng Jia,Yuqing Li,Yuhua Zhang,Jianguo Liao
Much attention has been paid to oxidising amyloid-β peptides (Aβ) for inhibiting their aggregation using photosensitive materials. However, the low penetration of ultraviolet/visible light into biological tissues and low targeting properties of the materials hinder their application. Here, we constructed a novel platform for attenuating the neurotoxicity of Aβ through functional upconversion nanoparticles (UCNPs@SiO2-ThS). UCNPs@SiO2-ThS can not only inhibit the aggregation of Aβ42 monomers, but also disassemble Aβ42 fibrils by its selective photooxidative capacity under the irradiation of near-infrared (NIR) light. Moreover, based on the enhancement of ThS fluorescence after attaching to Aβ42 fibrils, only Aβ42 fibrils exposed to both UCNPs@SiO2-ThS and light can be oxidized rather than other normal proteins. To further enhance Aβ-target photooxygenation, we introduced the Aβ-target peptide (KLVFF) on the surface. Compared to traditional chemotherapies and radiotherapies, this novel PDT strategy shows remarkably reduced side effects and improved targeting.
研究领域:
神经科学
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生物医学工程
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材料科学
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高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2023
·Vol. 24
·期 5
·5039
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IF 5.6
Lei Wang,Yuanyuan Cheng,Wenxia Wang,Jinwu Zhao,Yinsong Wang,Xumei Zhang,Meng Wang,Tianhe Shan,Mingxia He
The pathophysiology of Alzheimer’s disease is thought to be directly linked to the abnormal aggregation of β-amyloid (Aβ) in the nervous system as a common neurodegenerative disease. Consequently, researchers in many areas are actively looking for factors that affect Aβ aggregation. Numerous investigations have demonstrated that, in addition to chemical induction of Aβ aggregation, electromagnetic radiation may also affect Aβ aggregation. Terahertz waves are an emerging form of non-ionizing radiation that has the potential to affect the secondary bonding networks of biological systems, which in turn could affect the course of biochemical reactions by altering the conformation of biological macromolecules. As the primary radiation target in this investigation, the in vitro modeled Aβ42 aggregation system was examined using fluorescence spectrophotometry, supplemented by cellular simulations and transmission electron microscopy, to see how it responded to 3.1 THz radiation in various aggregation phases. The results demonstrated that in the nucleation aggregation stage, 3.1 THz electromagnetic waves promote Aβ42 monomer aggregation and that this promoting effect gradually diminishes with the exacerbation of the degree of aggregation. However, by the stage of oligomer aggregation into the original fiber, 3.1 THz electromagnetic waves exhibited an inhibitory effect. This leads us to the conclusion that terahertz radiation has an impact on the stability of the Aβ42 secondary structure, which in turn affects how Aβ42 molecules are recognized during the aggregation process and causes a seemingly aberrant biochemical response. Molecular dynamics simulation was employed to support the theory based on the aforementioned experimental observations and inferences.Keywords:THz radiation;Aβ;aggregation;molecular dynamics simulation;secondary structure
研究领域:
神经生物学
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生物物理学
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PubMed
高影响因子
CARBOHYDRATE RESEARCH
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2023
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IF 3.1
Jianrong Wu,Congsheng Wang,Tiantian Zhang,Hongtao Zhang,Xiaobei Zhan
In this work, a mannan-oligosaccharide conjugate with sialic acid capable of perturbing Aβ42 aggregation was designed and synthesized. Mannan oligosaccharides with degree polymerization of 3–13 were obtained by stepwise hydrolysis of locust bean gum using β-mannanase and α-galactosidase, named as LBOS. The activated LBOS was further chemically conjugated with sialic acid (Sia, N-acetylneuraminic acid) by fluoro-mercapto chemical coupling to synthesize a conjugate LBOS-Sia, and then phosphorylated to obtain pLBOS-Sia. The successful synthesis of pLBOS-Sia was confirmed by infrared1 chromatography, mass spectrometry, and 1 H NMR. The soluble protein analysis, microscopic observation, thioflavin T-labeling, and circular dichroism spectroscopy revealed that both LBOS-Sia and pLBOS-Sia can inhibit Aβ42 aggregation. MTT assay showed that LBOS-Sia and pLBOS-Sia had no cytotoxicity to BV-2 cells, and could substantially reduce the release of pro-inflammatory factor TNF-α induced by Aβ42 in BV-2 cells, and inhibit the occurrence of neuroinflammation. In future, this novel structure of mannan oligosaccharide-sialic acid conjugate can be potentially used to for the development of glycoconjugates against AD targeting Aβ.
研究领域:
生物化学
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神经科学
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药物化学
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PubMed
高影响因子
BRAIN RESEARCH
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2024
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IF 2.7
Xiaoyuan Ding,Fan Liu,Haohao Wang,Yan Wang,Guohui Li,Xingen Zhang,Cheng Song,Fucheng Zhu,Dong Liu
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Accumulation of β-amyloid (Aβ) in the brain has been recognized as a key factor in the onset and progression of Alzheimer’s disease (AD).The accumulation of Aβ in the brain catalyzes the production of reactive oxygen species (ROS), which in turn triggers oxidative damage to cellular components such as DNA, lipids, and proteins. In the present study, we investigated the protective effect of Ganoderic acid A (GA.A) against Aβ42-induced apoptosis in PC12 cells. Changes in mitochondrial membrane potential indicated that GA.A treats mitochondrial dysfunction by decreasing Aβ42 deposition and inhibiting neural protofiber tangle formation. Changes in intracellular Ca 2+ and caspase-3 indicated that GA.A reduced mitochondrial damage by Aβ42 in PC12 cells, thereby decreasing ROS accumulation and reducing Aβ protofiber-induced cytotoxicity. These features suggest that GA.A has great potential as an effective neuroprotective drug in the treatment of Alzheimer’s disease.
研究领域:
神经科学
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药理学
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PubMed
高影响因子
MICROCHIMICA ACTA
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2025
·Vol. 192
·期 1
·1-11
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IF 5.3
Zhang Junli,Zhao Yanyan,Hu Haiying,Lv Min,Zhang Hongling
A nano-enzyme sandwich assay (SWzyme assay), a colorimetric system based on a biochip and inorganic nano-enzyme for rapid and simple determination of exosomal Aβ42 in plasma is proposed. Anti-CD63 antibody-modified biochips were prepared for plasma exosome capture and synthesized highly catalytic Ni@Pt nanozymes for detecting exosomal Aβ42. The method was able to detect exosomal Aβ42 with a limit of detection (LOD) as low as 4.2×10 4 particles/mL and a linear range from 10 4 to 10 8 particles/mL. By determination of exosomal Aβ42, the SWzyme assay successfully distinguished plasma from Alzheimer’s desease (AD) and healthy mice. The SWzyme assay holds promise to serve as diagnostic tools for the early detection of AD and supporting the development of personalized medicine. Graphical abstract
研究领域:
生物化学
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医学诊断
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纳米技术
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DOI
PubMed
高影响因子
FITOTERAPIA
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2023
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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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PubMed
高影响因子
LANGMUIR
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2023
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IF 3.9
Qiong Li,Jing Wen,Ziyi Yan,Hang Sun,Erqun Song,Yang Song
Humans may intendedly or unintendedly be exposed to nanomaterials through food, water, and air. Upon exposure, nanomaterials can pierce the bloodstream and translocate to secondary organs, including the brain, which warrants increased concern for the potential health impacts of nanomaterials. Due to their large surface area and interaction energy, nanomaterials can adsorb surrounding proteins. The misfolding and self-aggregation of amyloid-β (Aβ) have been considered significant factors in the pathogenesis of Alzheimer’s disease. We thus hypothesize that brain-targeted nanomaterials may modulate Aβ aggregation and cause related neurotoxicity. Here, we showed that TiO2 nanoparticles (NPs) and their aminated analogue (TiO2-NH2 NPs) adsorb the Aβ42 peptide and accelerate its early oligomerization. Molecular dynamics simulation indicated that the adsorption onto TiO2 NPs and TiO2-NH2 NPs surfaces can stabilize the β-sheet-rich conformations formed by the Aβ42 peptide. The binding sites between TiO2-NH2 NPs and the Aβ42 oligomer surface were mainly concentrated in the hydrophobic core region, and the β-sheet conformation spontaneously formed by Aβ42 oligomers can be better stabilized through a hydrogen bond, electrostatic attraction, and hydrophobic interaction. This study will further help in the understanding of nanomaterial-related neurotoxicities and the regulation of their applications.
研究领域:
生物医学
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纳米毒理学
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蛋白质化学
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高影响因子
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
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2023
·Vol. 120
·期 19
·e2219994120
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IF 11.1
Xiao-Ke Yang,Fu-Li Zhang,Xue-Ke Jin,Yu-Ting Jiao,Xin-Wei Zhang,Yan-Ling Liu,Christian Amatore,Wei-Hua Huang
Glutamate (Glu) is the major excitatory transmitter in the nervous system. Impairment of its vesicular release by β-amyloid (Aβ) oligomers is thought to participate in pathological processes leading to Alzheimer’s disease. However, it remains unclear whether soluble Aβ42 oligomers affect intravesicular amounts of Glu or their release in the brain, or both. Measurements made in this work on single Glu varicosities with an amperometric nanowire Glu biosensor revealed that soluble Aβ42 oligomers first caused a dramatic increase in vesicular Glu storage and stimulation-induced release, accompanied by a high level of parallel spontaneous exocytosis, ultimately resulting in the depletion of intravesicular Glu content and greatly reduced release. Molecular biology tools and mouse models of Aβ amyloidosis have further established that the transient hyperexcitation observed during the primary pathological stage is mediated by an altered behavior of VGLUT1 responsible for transporting Glu into synaptic vesicles. Thereafter, an overexpression of Vps10p-tail-interactor-1a, a protein that maintains spontaneous release of neurotransmitters by selective interaction with t-SNAREs, resulted in a depletion of intravesicular Glu content, triggering advanced-stage neuronal malfunction. These findings are expected to open perspectives for remediating Aβ42-induced neuronal hyperactivity and neuronal degeneration.
研究领域:
神经科学
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生物化学
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分子生物学
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高影响因子
ANALYTICAL CHEMISTRY
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2021
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IF 6.986
Yuemei Duan,Jia Chen,Yan Jin,Qiuyun Tu,Shuhui Wang,Juan Xiang
Alzheimer’s disease (AD) is the most common neurodegenerative disease among the elderly. Abnormal aggregates of both β-amyloid peptide (Aβ) subtypes, Aβ42 and Aβ40, are the typical neuropathology hallmarks of AD. However, because of the lack of specific recognition elements such as an antibody and aptamer, it is difficult to differentiate and determine the oligomers of Aβ42 and Aβ40 in clinic. In this paper, we developed a planar bilayer lipid membrane (BLM)-based electrochemical biosensor. According to the dynamic differences on oligomer-induced BLM damage, both low-mass, soluble oligomers of Aβ42 and Aβ40 (L-Aβ42O and L-Aβ40O) were measured in turn by electrochemical impedance spectroscopy. The BLM was supported by a porous 11-mercaptoundecanoic acid layer on a gold electrode, which amplified the impedance signal corresponding to the membrane damage and improved the detection sensitivity. The weakly charged surface of the BLM ensured the low non-specific adsorption of coexisting proteins in cerebrospinal fluid (CSF). Using the electrochemical biosensor, L-Aβ42O was determined within 20 min, with a linear range from 5 to 500 pM and a detection limit of 3 pM. Meanwhile, L-Aβ40O was determined within 60 min, with a linear range from 60 pM to 6.0 nM and a detection limit of 26 pM. The recoveries in oligomer-spiked artificial CSF and human CSF samples confirmed the accuracy and applicability of this proposed method in clinic. This work provides an antibody-free, highly selective, and sensitive method for simultaneous detections of L-Aβ42O and L-Aβ40O in real CSF samples, which is significant for the early diagnosis and prognosis of AD.
研究领域:
神经科学
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生物医学工程
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分析化学
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高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2023
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IF 3.1
Chunying Guo,Ting Wang,Dongmei Zhang,Xiaojing Ge,Jinan Li
Alzheimer's disease (AD) is the most common neurodegenerative disorder in the world. The aggregation of both amyloid beta (Aβ) peptides extracellularly and Tau proteins intracellularly plays key roles in the pathological consequences of AD, which lead to cholinergic neurodegeneration and eventually death. Currently, there are no effective methods to stop the progression of AD. Using ex vivo , in vivo and clinical approaches, we investigated the functional effects of plasminogen on the widely used FAD, Aβ42 oligomer or Tau intracranial injection-induced AD mouse model and explored its therapeutic effects on patients with AD. The results show that intravenously injected plasminogen rapidly crosses the blood‒brain barrier (BBB); increases plasmin activity in the brain; colocalizes with and effectively promotes the clearance of Aβ42 peptide and Tau protein deposits ex vivo and in vivo ; increases the choline acetyltransferase (ChAT) level and decreases the acetylcholinesterase (AChE) activity; and improves the memory functions. Clinically, when GMP-level plasminogen was administered to 6 AD patients for 1–2 weeks, their average scores on the Minimum Mental State Examination (MMSE), which is a standard scoring system used to measure the memory loss and cognitive deficits, were extremely significantly improved by 4.2 ± 2.23 points, e.g., an average increase from 15.5 ± 8.22 before treatment to 19.7 ± 7.09 after treatment. The preclinical study and pilot clinical study suggest that plasminogen is effective in treating AD and may be a promising drug candidate.
研究领域:
神经科学
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药理学
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临床试验
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PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2024
·Vol. 22
·期 1
·1-19
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IF 10.6
Zhang Liding,Cao Kai,Xie Jun,Liang Xiaohan,Gong Hui,Luo Qingming,Luo Haiming
Amyloid-β (Aβ) readily misfolds into neurotoxic aggregates, generating high levels of reactive oxygen species (ROS), leading to progressive oxidative damage and ultimately cell death. Therefore, simultaneous inhibition of Aβ aggregation and scavenging of ROS may be a promising therapeutic strategy to alleviate Alzheimer’s disease pathology. Based on the previously developed antibody 1F12 that targets all forms of Aβ 42 , we developed an Aβ 42 and ROS dual-targeting nanocomposite using biodegradable mesoporous silica nanoparticles as carriers to load ultra-small cerium oxide nanocrystals (bMSNs@Ce-1F12). By modifying the brain-targeted rabies virus glycoprotein 29 (RVG29-bMSNs@Ce-1F12), this intelligent nanocomposite can efficiently target brain Aβ-rich regions. Combined with peripheral and central nervous system treatments, RVG29-bMSNs@Ce-1F12 can significantly alleviate AD symptoms by inhibiting Aβ 42 misfolding, accelerating Aβ 42 clearance, and scavenging ROS. Furthermore, this synergistic effect of ROS scavenging and Aβ clearance exhibited by this Aβ 42 and ROS dual-targeted strategy also reduced the burden of hyperphosphorylated tau, alleviated glial cell activation, and ultimately improved cognitive function in APP/PS1 mice. Our findings indicate that RVG29-bMSNs@Ce-1F12 is a promising nanodrug that can facilitate multi-target treatment of AD.
研究领域:
神经科学
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纳米技术
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药学
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分子生物学
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治疗学
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PubMed
高影响因子
ACS Applied Bio Materials
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2020
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IF 0
Chang Liu,Xinrui You,Dingkun Lu,Guoyue Shi,Jingjing Deng,Tianshu Zhou
Nowadays, the environmental risk factors for Alzheimer’s disease (AD) have received widespread attention. Two major amyloid-β peptide (Aβ) variants, Aβ42 and Aβ40, play a pivotal role in the etiology of AD and the concentration ratio of which (i.e., Aβ42%) has been suggested to be the superior biomarker for AD. In this study, an “aggregation-based colorimetric sensor array” for the simultaneous identification and detection of Aβ40 and Aβ42 with structural similarity was established based on gelsolin-modified silver nanotriangles (Ag NTs) and silver nanorods (Ag NRs). Different aggregation behaviors of gelsolin-modified Ag NTs and Ag NRs in the presence of Aβ42 and Aβ40 resulted in different color and spectral changes, which could be quantitatively analyzed in terms of unique spectral patterns by principal component analysis. With the colorimetric sensor array employed here, the fluctuation of Aβ42% in different brain regions of rats exposed to Cd2+ could be directly monitored. The downward trend of Aβ42% accompanied by variations of other biochemical indicators suggested that subchronic Cd2+ exposure possibly triggered the onset of AD through the intervention of lipid peroxidation pathway. Furthermore, in vivo monitoring the downtrend of Aβ42% in cerebrospinal fluid (CSF) could also be realized, which offers a great opportunity for early diagnosis and treatment of AD that may be induced by environmental factors with CSF Aβ42% as a reliable indicator.
研究领域:
纳米技术
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神经科学
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环境健康
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分析化学
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疾病诊断
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PubMed
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