CNS Neuroscience & Therapeutics
·
2017
·Vol. 23
·期 6
·498-509
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IF 3.919
Cui Huang,Dong Dong,Qian Jiao,Hui Pan,Lei Ma,Rui Wang
Summary Aims Sarsasapogenin has been reported to improve dementia symptoms somehow, probably through modulating the function of cholinergic system, suppressing neurofibrillary tangles, and inhibiting inflammation. However, the role of sarsasapogenin in response to beta-amyloid (A β ) remains to be delineated. This study aimed to determine the therapeutic effect of sarsasapogenin-13 (AA13, a sarsasapogenin derivative) on learning and memory impairments in A β -injected mice, as well as the role of AA13 in neuroglia-mediated antiinflammation and A β clearance. Methods Focusing on the role of AA13 in regulating glial responses to A β , we conducted behavioral, morphological, and protein expression studies to explore the effects of AA13 on A β clearance and inflammatory regulation. Results The results indicated that oral administration of AA13 attenuated the memory deficits of intracerebroventricular (i.c.v.) A β -injected mice; also, AA13 protected neuroglial cells against A β -induced cytotoxicity. The further mechanical studies demonstrated that AA13 reversed the upregulation of proinflammatory M1 markers and increased the expression of antiinflammatory M2 markers in A β -treated cells. Furthermore, AA13 facilitated A β clearance through promoting A β phagocytosis and degradation. AA13 modulated the expression of fatty acid translocase (CD36), insulin-degrading enzyme (IDE), neprilysin (NEP), and endothelin-converting enzyme (ECE) in neuroglia. Conclusion The present study indicated that the neuroprotective effect of AA13 might relate to its modulatory effects on microglia activation state, phagocytic ability, and expression of A β -degrading enzymes, which makes it a promising therapeutic agent in the early stage of Alzheimer's disease (AD).
研究领域:
神经科学
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药理学
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神经退行性疾病
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DOI
PubMed
高影响因子
NEURON
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2022
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IF 18.688
Jin Hu,Qiang Chen,Hongrui Zhu,Lichao Hou,Wei Liu,Qihua Yang,Huidan Shen,Guolin Chai,Boxin Zhang,Shaoxuan Chen,Zhiyu Cai,Chongxin Wu,Fan Hong,Hongda Li,Sifang Chen,Naian Xiao,Zhan-xiang Wang,Xueqin Zhang,Bo Wang,Liang Zhang,Wei Mo
Summary The pathology of Alzheimer’s disease (AD) is featured with extracellular amyloid-β (Aβ) plaques, whose impact on the mechanical properties of the surrounding brain tissues is unclear. Microglia sense and integrate biochemical cues of the microenvironment. However, whether the microglial mechanosensing pathways influence AD pathogenesis is unknown. Here, we surveyed the elevated stiffness of Aβ-plaque-associated tissues and observed the selective upregulation of the mechanosensitive ion channel Piezo1 in Aβ-plaque-associated microglia. Piezo1 sensed the stiffness stimuli of Aβ fibrils and subsequently induced Ca 2+ influx for microglial clustering, phagocytosis , and compacting of Aβ plaques. Microglia lacking Piezo1 led to the exacerbation of Aβ pathology and cognitive decline, whereas pharmacological activation of microglial Piezo1 ameliorated brain Aβ burden and cognitive impairment in 5 × FAD mice. Together, our results reveal that Piezo1, a mechanosensor of Aβ fibril stiffness in microglia, represents a potential therapeutic target for AD.
研究领域:
神经科学
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病理学
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细胞生物学
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DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
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2025
·
IF 8.4
Feng Yue-yao,Hao Jing-ran,Zhang Yu-jie,Qiu Tong-tong,Zhang Meng-lin,Qiao Wei,Wu Jin-jin,Qiu Ping,Xu Chao-fan,Zhang Yin-liang,Du Chun-yuan,Pan Zhe,Chang Yong-sheng
The deposition of β-amyloid (Aβ) in the brain is a crucial factor in the pathogenesis of Alzheimer’s disease (AD). Insulin-degrading enzyme (IDE) plays a critical role in the balance between Aβ production and degradation. However, the regulatory mechanisms of IDE are not yet fully understood. Therefore, uncovering additional IDE regulatory mechanisms will help elucidate the pathogenesis of AD and identify key therapeutic targets for this disease. This study revealed that global Krüppel-like factor 9-mutant (Klf9 −/− ) mice exhibited impaired cognitive function. Additionally, we found that Klf9 expression in hippocampal tissue was reduced in APPswe/PS1dE9 (APP/PS1) mice. This study also showed that Klf9 stimulates IDE expression and promotes the Aβ degradation process by directly binding to IDE and activating its transcription. Silencing IDE blocked the Klf9-induced Aβ degradation process. We stereotactically injected an adeno-associated virus to selectively overexpress IDE (AAV-IDE) in the hippocampal neurons of Klf9 −/− mice and found that the overexpression of IDE in hippocampal neurons ameliorated cognitive deficits and reduced the Aβ content in Klf9 −/− mice. Additionally, we also stereotactically injected AAV-Klf9 into the hippocampal neurons of APP/PS1 mice and found that overexpression of Klf9 in hippocampal neurons ameliorated cognitive deficits and reduced Aβ levels in APP/PS1 mice. These findings suggest that downregulation of Klf9 may be a key factor in AD progression, as it reduces Aβ clearance by decreasing IDE expression. Overexpression or activation of Klf9 may be a potential strategy for preventing the pathogenesis of AD.
研究领域:
神经生物学
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分子生物学
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医学
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产品关联
DOI
PubMed
高影响因子
LANGMUIR
·
2024
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IF 3.7
Shenna Chen,Ronghui Li,Yanxu Liu,Ziyan Zhang,Mei Fang,Sihang Huang,Yayong Li,Lina Geng
Multifunctional nitrogen-doped carbon dots (N-CDs) were synthesized, and the morphology, composition, and spectral properties of N-CDs were characterized by multiple characterization techniques. The inhibition of β-amyloid (Aβ) peptide aggregation and the destruction of the Aβ fibril structure by N-CDs were also studied. The conformational transition and morphology of Aβ42 in the presence of N-CDs were monitored by far-UV circular dichroism (CD) spectroscopy and transmission electron microscopy (TEM). The results demonstrated that the prepared N-CDs could effectively inhibit Aβ42 peptide aggregation and depolymerize Aβ fibrils. Furthermore, the inhibition and disaggregation mechanism of existing Aβ42 fibrils by N-CDs was studied by electron paramagnetic resonance spectroscopy (EPR). The results showed that the modulation of reactive oxygen species (ROS) by N-CDs and multiple interactions between N-CDs and Aβ42 fibrils played a crucial part in restraining and reducing the aggregation of Aβ42. Our work demonstrates the therapeutic potential of N-CDs in suppressing Aβ42 peptide aggregation and destroying existing Aβ42 fibrils, which provides a new perspective strategy in the treatment of Alzheimer’s disease (AD).
研究领域:
生物化学
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医学
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材料科学
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产品关联
DOI
PubMed
高影响因子
TALANTA
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2018
·
IF 4.244
Qichen Zhan,Xianqing Shi,Ting Wang,Jinhui Hu,Jiahong Zhou,Lin Zhou,Shaohua Wei
The formation and accumulation of toxic amyloid beta (Aβ) protofibrils in brain is recognized as the pathological hallmark of alzheimer’s disease (AD). Recent research indicated that photodynamic therapy (PDT) has potential to treat AD because reactive oxygen species (ROS) generated by photosensitizers (PS) could degrades Aβ protofibrils. Al 3+ and Fe 3+ were found at markedly high levels on and around Aβ protofibrils comparing with the normal part of brain. Based on this, a thymine modified Zn phthalocyanine (T-ZnPc), which can specific recognize and has strong affinity with Fe 3+ and Al 3+ , was designed and synthesized. The recognize, affinity, Aβ protofibrils degradation and neuro protection process were monitored via ultraviolet absorption spectrometry (UV), fluorescence emission spectrum, transmission electron microscopy (TEM), flow cytometer and thiazolyl blue tetrazolium bromide (MTT) assay. The results revealed that such affinity effect greatly increases the molar extinction coefficient (from 1.70 × 10 4 to 4.67 × 10 4 and 3.30 × 10 4 after forming Fe-T-ZnPc and Al-T-ZnPc) and activates PDT activity of T-ZnPc to generate abundant ROS to degrade Aβ protofibrils (62% and 81% degradation by Al-T-ZnPc and Fe-T-ZnPc) and prevent its neurotoxicity based on the statistical differences analysis. Besides, T-ZnPc could inhibit new Aβ protofibrils formation and the chelation effect could reduce the free Fe 3+ and Al 3+ concentration in brain, which could be also helpful for AD treatment.
研究领域:
神经科学
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分子生物学
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药物化学
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生物物理学
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DOI
PubMed
高影响因子
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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产品关联
DOI
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2014
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IF 3.096
Di Zhang,Hua Li,Jian-Bo Wang
Amyloid protein depositions play crucial roles in a variety of degenerative disorders composing amyloidosis . There is a great interest in developing small molecule inhibitors of amyloidogenic processes. We examined the inhibitory effects of echinacoside (ECH) with different concentrations and at different fiber-forming stages in vitro utilizing the hen egg-white lysozyme (HEWL) model system. We also evaluated the antioxidant capacity of ECH by using elimination tests for the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl ( HO) free radicals. We investigated the protection provided by ECH against neurotoxicity induced by β-amyloid protein (Aβ). Through spectroscopic analyses, electron microscopy , cell viability assay, and hemolysis assay, we found that ECH dose dependently inhibited HEWL aggregation, and this inhibition occurred in different fiber-forming stages. ECH could also scavenge the DPPH and OH free radicals in a concentration-dependent manner. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and 2′,7′-dichlorodihydrofluoresceindiacetate (DCFH-DA) fluorescent measurement results indicated that ECH could increase viability of rat pheochromocytoma PC12 cells injured by Aβ and suppress the increase in intracellular reactive oxygen species (ROS) triggered by Aβ. The present study findings facilitate a better understanding of the interaction between ECH and amyloid-forming proteins and also shed light on the protection of ECH against amyloid fibril-induced neuronal cell death.
研究领域:
生物化学
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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
MOLECULAR IMMUNOLOGY
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2018
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IF 3.188
Lu Fu,Yongqing Guo,Yao Sun,Yue Dong,Jiaxin Wu,Bin Yu,Haihong Zhang,Xianghui Yu,Hui Wu,Wei Kong
Amyloid-beta (Aβ) plaque accumulation in the brain is one of the hallmarks of Alzheimer’s disease (AD). Immunotherapy against Aβ was considered a potential strategy for reducing the Aβ load in the brain. However, none of the Aβ immunotherapies have produced clinically meaningful results to date, due to poor safety or lack of efficacy. Thus, we aimed to design a safe and effective vaccine against AD. In this study, we used bacterium-like particles (BLPs) as carriers and different copy numbers of the Aβ 1-6 peptide as epitopes to design four Aβ active immunization vaccines. The epitopes containing different copy numbers of the Aβ 1-6 peptide were specifically loaded on the surface of BLPs via fusion with a peptidoglycan anchoring domain. These four BLP-based Aβ vaccines successfully induced high levels of Aβ42-specific antibodies in mice. However, none of the vaccines induced a T-cell-mediated immune response. Importantly, the antibodies induced by these four vaccines were effective in blocking Aβ42 oligomer toxicity at the cellular level. Among the four vaccines, 6copy-Aβ 1-6 -PA-BLP was the most effective in inducing Aβ-specific antibodies, indicating that a suitable epitope copy number is critical for high immunogenicity of the BLP-based vaccine. Furthermore, high levels of serum Aβ-specific antibodies could still be detected 3 months after the final administration of 6copy-Aβ 1-6 -PA-BLP. Thus, 6copy-Aβ 1-6 -PA-BLP may be a potential therapeutic treatment for AD.
研究领域:
生物医学
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神经科学
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疫苗开发
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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
MEDICAL SCIENCE MONITOR
·
2018
·
IF 1.894
Zeng Li,Xiao-chang Liu,Rui Li,Jun Chang
Background Beta-secretase 1 (BACE1) is a rate-limiting enzyme in the generation of amyloid beta peptides, which are associated with Alzheimer’s disease (AD). It has been reported that Schisandrin B could improve cognitive functions in animal models of AD, but the underlying mechanisms are not completely understood. Material/Methods In this research, in order to investigate the effects of Schisandrin B on amyloid-β (Aβ) metabolism and its mechanisms, amyloid precursor protein (APP) and its proteolytic products were determined by enzyme-linked immunosorbent assay (ELISA), western blotting, and RT-PCR after incubation of N2a/Swe cells with Schisandrin B. Results The results indicated that Schisandrin B can significantly reduce the level of secretion of Aβ 40 and Aβ 42 secreted in N2a/Swe cells. Additionally, there was nonsignificant change in APP level after Schisandrin B treatment. Treatment of Schisandrin B dramatically reduced the mRNA and protein expression levels of BACE1. Moreover, Schisandrin B treatment resulted in a reduction of protein level of sAPPβ, an APP fragment cleavage by BACE1. Conclusions These results suggest that Schisandrin B inhibits the transcription and translation of BACE1, suppresses the activity of BACE1, and ultimately attenuates Aβ generation, which provides a novel mechanism for the regulation of Aβ metabolism by Schisandrin B.
研究领域:
神经生物学
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分子药理学
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神经退行性疾病研究
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药物代谢
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生物化学
✓ 已验证
DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
·
2022
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IF 8.008
Qiwen Peng,Min Zhang,Guoyue Shi
An amyloid-beta peptide (Aβ) is generally believed to be a pathological marker of Alzheimer’s disease (AD), but it is still of great significance to explore the upstream and downstream relationship of Aβ in AD. It is previously reported that c-Abl, a nonreceptor tyrosine kinase, can be activated by Aβ, but the interaction between Aβ and c-Abl is still unknown. Herein, an extended-gate field-effect transistor (EG-FET)-based sensor has been developed to monitor the level of c-Abl with high sensitivity and selectivity. Our peptide-functionalized EG-FET sensor as the signal transducer can follow c-Abl activity with electron transfer by its specific phosphorylation. The sensor presents a good linear correlation over c-Abl concentrations of 1 pg/mL to 3.05 μg/mL. The sensor was successfully applied to quantify c-Abl activity in the brain tissue of AD transgenic mice, and the interaction between c-Abl and Aβ in AD mice was explored by administering the c-Abl inhibitor (imatinib) and the agonist (DPH). Our work is expected to provide an important reference for early diagnosis and treatment of AD.
研究领域:
生物医学工程
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神经科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
DYES AND PIGMENTS
·
2025
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IF 4.2
Pengbo She,Lei Xing,Mingyang Zhou,Shu Xing,Yaozheng Yang,Xiuxiu Li,Xuanxuan Ma,Tao Cheng,Jinjian Wei,John K. Bielicki,Jing Xu
The utilization of near-infrared fluorescent probes for the detection of amyloid-β (Aβ) in Alzheimer's disease (AD) has been extensively investigated. Nevertheless, the development of probes that can simultaneously meet the requirements for rapid, accurate, and visual detection remains challenging. In this study, a novel Aβ-targeted fluorescent probe, designated NQM-FN , has been designed based on a D-π-A structural framework. NQM-FN incorporates quinoline-malononitrile (QM) as the fluorescent component and N,N- dimethylmino as the recognition unit. By utilizing a push-pull electronic conjugation system (with N,N- dimethylmino as electron donor; sulfonic acid and cyanide groups as electron acceptors), NQM-FN induces near-infrared emission and enhances blood-brain barrier (BBB) permeability. Fluorescence analysis indicated that NQM-FN is non-emissive in aqueous environments due to aggregation-caused quenching (ACQ), yet it demonstrates robust fluorescence in organic solvents, such as ethanol. When bound to Aβ aggregates, conformational rigidification suppresses twisted intramolecular charge transfer (TICT), facilitating rapid ‘off-on’ detection with increased emission intensity. NQM-FN interacts with Aβ42 aggregates in PBS solution, showing a rapid “off-on” switch (approximately 10 s). MTT assays revealed that the NQM-FN probe has good cellular compatibility, sustaining over 80 % cell viability. Confocal laser scanning microscopy (CLSM) imaging confirmed the successful real-time, sensitive, and visual detection of Aβ42 aggregates within live cells using the NQM-FN probe. This research introduces an innovative method for synthesizing fluorescent probes for the detection of Aβ42 aggregates, and the developed NQM-FN probe shows great promise as a tool for fluorescent detection.
研究领域:
生物化学
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医学诊断
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分子探针设计
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）