FOLIA NEUROPATHOLOGICA
·
2020
·Vol. 58
·期 1
·10-21
·
IF 1.278
Chengyan Sun,Ning Jia,Rui Li,Ze Zhang,Yi Zhong,Kun Han
IntroductionAlzheimer’s disease (AD) is still the fifth leading cause of death and most common dementia worldwide. To date, there is no efficient strategy that can slow down the progression of AD owing to delayed diagnosis and limited therapies. MiR-143-3p is up-regulated in serum of AD patients, yet the exact role it plays in AD pathology is still poorly understood. The aim of this study was to investigate the effect of miR-143-3p on neuronal survival.Material and methodsWe induced neuronal differentiation in SH-SY5Y cells using all-trans-retinoic acid (RA), and Aβ1-42 was used to establish the in vitro AD cell model. The expression of tubulin β III and neuregulin-1 (NRG1) was evaluated by immunofluorescence. TUNEL assay was performed to assess cell apoptosis. Cell viability was evaluated using the Cell Counting Kit-8 assay. The binding interaction between miR-143-3p and NRG1 was verified using the luciferase reporter assay.ResultsTypical neuronal-like axons were observed in RA-induced SH-SY5Y cells, followed by increased tubulin β III. A dramatically increased apoptotic rate and reduced cell viability were observed in the AD cell model. Then we silenced the miR-143-3p expression, and Aβ1-42 induced cell apoptosis was alleviated after miR-143-3p inhibition, accompanied by decreased cleaved caspase-3 and cleaved caspase-9 levels. Additionally, NRG1 was confirmed to be a downstream target of miR-143-3p, increased cell viability and suppressed cell apoptosis after miR-143-3p inhibition was abolished by NRG1 knockdown.ConclusionsOur findings reveal that miR-143-3p inhibition promotes neuronal survival in an in vitro cell model via targeting NRG1, and the miR-143-3p/NRG1 axis is a potential therapeutic target and promising biomarker for AD treatment.
研究领域:
神经科学
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分子生物学
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细胞生物学
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神经退行性疾病
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PubMed
高影响因子
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
·
2020
·Vol. 393
·期 9
·1739-1752
·
IF 2.05
Song Lin,Yao Lifen,Zhang Limei,Piao Zhongyuan,Lu Yichan
Autophagy, a lysosomal degradative pathway, is crucial for the pathogenesis of Alzheimer’s disease (AD). Schizandrol A (SchA) shows multiple pharmacological effects. However, the potential effects and mechanisms of SchA on amyloid-β (Aβ)-induced autophagy remain unclear. In this study, differentiated SH-SY5Y cells or primary hippocampal neurons were pretreated with SchA (2 μg/ml) for 1 h before subjected to Aβ 1–42 (10 μM) for 24 h to test its effects on cell viability, apoptosis, oxidative stress, and autophagy. Then an mTOR inhibitor (rapamycin) and a PI3K inhibitor (LY294002) were employed to explore the role of PI3K/AKT/mTOR pathway. The results showed that SchA significantly inhibited Aβ 1–42 -triggered reduction of viable cells, increases of apoptotic cell number and pro-apoptotic protein expressions, as well as alterations of oxidative stress markers. In addition, the increases of LC3-II/LC3-I and Beclin-1 and decrease of p62 were suppressed by SchA. At the molecular level, we found that the inactivation of PI3K/AKT/mTOR pathway was ameliorated by SchA. Inhibition of PI3K/AKT/mTOR pathway deteriorated the protective effects of SchA against Aβ 1–42 -induced autophagy activation, cell death, and apoptosis. In conclusion, we demonstrate that SchA attenuates Aβ 1–42 -induced autophagy through activating PI3K/AKT/mTOR signaling pathway. SchA may be a novel drug for the prevention and treatment of AD.
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Food Bioscience
·
2026
·
IF 5.9
Lixia Ma,Dina Chang,Jiaxin Lv,Yan Yan,Anxu Zheng,Xuehang Wang,Yue Leng,Bin Jiang,Dayong Ren,Ji Wang
Walnuts are nutrient-dense with diverse physiological functions. This study developed a walnut-milk dual-protein yogurt (WY) using Lactiplantibacillus plantarum JLAU103, investigating its refrigerated storage (4 °C) properties, microstructure, volatile profile, sensory traits, antioxidant activity, and isolating antioxidant peptides. The WY exhibited excellent storage stability over a 21-day period, maintaining an optimal and stable pH range of 4.48–4.78 and titratable acidity of 63.3–72.66 °T. Compared with the MY control, WY showed markedly reduced syneresis, enhanced water-holding capacity, and superior textural and viscosity properties, while sustaining viable L. plantarum JLAU103 populations above 10 7 CFU/mL. Rheological and microstructural analyses showed WY had higher elastic (G′)/viscous (G″) moduli and a denser protein network, enhancing gel stability. WY contained 200 volatile compounds, with higher aldehydes/furans (key for nutty/roasted aromas) and better sensory acceptability than MY. Ultrafiltration fractionated WY proteins into <3 kDa (superior antioxidant) and 3–10 kDa fractions; the <3 kDa fraction was purified to sub-fraction B1, which exhibited strong radical scavenging (ABTS + : 15.86 %, DPPH: 53.48 %, •OH: 48.21 %) and Fe 2+ chelating (98.23 %) capacities. Nano-LC-MS/MS identified 1972 peptides in B1, 10 peptides with predicted antioxidant activity via BIOPEP-UWM. Peptide GPYHFR bound Aβ 1-42 oligomers (−7.7 kcal/mol), showing potential to mitigate memory impairment. This study provides a theoretical/technical basis for high-quality functional walnut fermented dairy products and walnut bioactive peptide exploitation.
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Science Advances
·
2024
·Vol. 10
·期 13
·
IF 11.7
Shun Hu,Liding Zhang,Ying Su,Xiaohan Liang,Jie Yang,Qingming Luo,Haiming Luo
Blood exosomes are emerging as potential biomarkers for diagnosing brain diseases such as Alzheimer’s disease (AD). There is currently a lack of an ultrasensitive technology for identifying core AD biomarkers in blood exosomes to optimize the utility of biomarkers in clinical practice. Here, an immunomagnetic exosomal polymerase chain reaction (iMEP) platform was developed using DNA-conjugated antibodies for the rapid detection of amyloid-β (Aβ1–40 and Aβ1–42) and phosphorylated tau (p-tau396,404 and p-tau181) in clinical blood exosomes. The toehold shift–mediated DNA affinity pulldown eliminates the high detection background, which allows the detection of biomarkers at concentrations down to 10 femtograms per milliliter. With the iMEP assay, exosomal Aβ1–42 was more accurate in differentiating patients with AD from healthy individuals compared with exosomal p-tau181 and p-tau396,404, with a sensitivity of 95.0% and a specificity of 95.0%. The iMEP technique is also adept at quantifying the levels of different exosomal biomarkers associated with disease pathogenesis.
研究领域:
神经科学
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分子生物学
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临床诊断
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生物标志物研究
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PubMed
高影响因子
ANALYST
·
2018
·Vol. 144
·期 2
·504-511
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IF 3.864
Yin Zhang,Si Meng,Jinhua Ding,Qiwen Peng,Yanyan Yu
Herein, we developed a sensitive graphitic carbon nitride quantum dot (gCNQD)-based fluorescent strategy for β-amyloid peptide monomer (Aβ) determination down to the ng mL−1 level for the first time. To realize this goal, the nanostructured gCNQDs were firstly coordinated with four transition metal ions (Cu2+, Cu+, Fe3+, Zn2+). Our findings showed that the fluorescence (FL) intensity of gCNQDs was quenched in the presence of these metal ions possibly due to the effective chelation with the nitrogen element in gCNQDs and subsequent photoinduced electron transfer (PET) of gCNQDs. The degree of fluorescence quenching was found to be the most intense with the addition of Cu2+ and therefore, we selected Cu2+ as the quencher for the following Aβ determination. Through binding to Cu2+, the introduction of Aβ unexpectedly induced a further decline of FL intensity. Importantly, on account of different peptide sequences coexisting in the same cerebral system, including Aβ1–11, Aβ1–16, Aβ1–38, Aβ1–40 and Aβ1–42, their affinities to Cu2+ could be reflected by the distinguished declining extent of FL intensity. The possible mechanism of Aβ sensing by the probe was clarified by TEM characterization. The developed fluorescent biosensor was demonstrated to give a wide linear range from 1 to 700 ng mL−1 and a low detection limit of 0.18 ng mL−1 for Aβ1–42. In the end, the proposed fluorescence approach was successfully applied to monitoring of Aβ1–42 variations in the cortex and hippocampus of AD rats.
研究领域:
材料科学
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分析化学
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生物技术
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神经科学
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高影响因子
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
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2022
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IF 5.756
Huan-Huan Li,Chengyao Wu,Shi-Long Zhang,Jian-Guo Yang,Hua-Li Qin,Wenjian Tang
Novel scaffolds are expected to treat Alzheimer’s disease, pyrazole-5-fluorosulfates were found as selective BuChE inhibitors. Compounds K1–K26 were assayed for ChE inhibitory activity, amongst them, compound K3 showed potent BuChE and hBuChE inhibition (IC50 = 0.79 μM and 6.59 μM). SAR analysis showed that 1-, 3-, 4-subtituent and 5-fluorosulfate of pyrazole ring affected BuChE inhibitory activity. Molecular docking showed that the fluorosulfate increased the binding affinity of hBuChE through π-sulphur interaction. Compound K3 was a reversible, mixed and non-competitive BuChE inhibitor (Ki = 0.77 μM) and showed remarkable neuroprotection, safe toxicological profile and BBB penetration. In vivo behavioural study showed that K3 treatment improved the Aβ1 − 42-induced cognitive impairment, and significantly prevented the effects of Aβ1 − 42 toxicity. Therefore, selective BuChE inhibitor K3 has potential to be further developed as AD therapeutics.
研究领域:
药理学
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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
Aging-US
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2023
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IF 5.2
Guang-Zhi Liu,Tian-Tong Niu,Qian Yu,Bao-Lei Xu,Xiao-Qing Li,Bo-Yi Yuan,Guo-Bin Yuan,Ting-Ting Yang,Hui-Qin Li,Yi Sun
The NLRP3 inflammasome is involved in the neuroinflammatory pathway of Alzheimer’s disease (AD). The aim of this study is to explore the roles and underlying mechanisms of ginkgolide (Baiyu®) on amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice and a murine microglial cell line, BV-2. In the present study, the APP/PS1 mice were administered with ginkgolide, followed by a Morris water maze test. The mice were then euthanized to obtain brain tissue for histological and Aβ analysis. Additionally, BV-2 cells were pretreated with ginkgolide and then incubated with Aβ1–42 peptide. NLRP3, ASC, and caspase-1 mRNA and protein expression in brain tissue of mice and BV-2 cells were quantified by real-time PCR and western blotting, as well as reactive oxygen species (ROS) production, interleukin (IL)-1β and IL-18 levels by lucigenin technique and ELISA. Compared with the APP/PS1 mice, ginkgolide-treated mice demonstrated the shortened escape latency, reduced plaques, less inflammatory cell infiltration and neuron loss in the hippocampi of APP/PS1 mice. The levels of NLRP3, ASC, caspase-1, ROS, IL-1β, and IL-18 were also decreased in the brain tissue of APP/PS1 mice or Aβ1–42-treated BV-2 cells following ginkgolide treatment. Ginkgolide exerted protective effects on AD, at least partly by inactivating the NLRP3/caspase-1 pathway.
研究领域:
神经科学
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药理学
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分子生物学
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PubMed
高影响因子
MOLECULES
·
2023
·Vol. 28
·期 3
·1451
·
IF 4.6
Hong Liu,Huazhang Guo,Yibin Fang,Liang Wang,Peng Li
The fibrillization and abnormal aggregation ofβ-amyloid (Aβ) peptides are commonly recognized risk factors for Alzheimer’s disease (AD) brain, and require an effective strategy to inhibit the Aβdeposition and treat AD. Herein, we designed and synthesized nitrogen-doped carbon dots (N-CDs) as an Aβ-targeted probe, which exhibits the capacity of inhibiting the 1–42 Aβ(Aβ1–42) self-assembly in vitro. The N-CDs exhibited orange emission with an emission wavelength of 570 nm, which demonstrates their excellent optical properties with excitation-independent behavior. Meanwhile, the N-CDs have spherical morphologies with an average size of 2.2 nm, whose surface enriches the amino, carboxyl, and hydroxyl groups. These preparties are conducive to improving their biological water solubility and provide a large number of chemical bonds for further interaction with proteins. Contrary to this, the kinetic process, size evolutions, and morphologies changes of Aβ1–42were inhibited in the presence of N-CDs in the determination of a thioflavin T assay, dynamic light scattering, transmission electron microscope, etc. Finally, the safety application of N-CDs on Aβ1–42-induced cytotoxicity was further demonstrated via in vitro cytotoxicity experiments. This work demonstrates the effective outcome of suppressing Aβaggregation, which provides a new view into the high-efficiency and low-cytotoxicity strategy in AD theranostics.Keywords:Alzheimer’s disease;carbon dots;nitrogen-doped;β-amyloid;aggregation
研究领域:
神经科学
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材料科学
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生物医学工程
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PubMed
高影响因子
ACS Sensors
·
2025
·
IF 9.1
Yue Cheng,Limoran Tang,Yi Tan,Hongpan Xu,Dan Yang,Zhixin Zhou,Wenqian Gao,Zhihong Ke,Chenglu Mao,Zheqi Hu,Hao Chen,Han Shen,Peng Cheng,Shujuan Xu,Yun Xu
Sensitive detection of low-abundance biomarkers in blood is essential for the early diagnosis of Alzheimer’s disease (AD). Although the single molecule array (Simoa) platform offers femtomolar-level sensitivity and surpasses conventional assays such as enzyme-linked immunosorbent assay, its broader clinical utility is constrained by issues like nonspecific binding and a limited dynamic range. In this study, we present a surface-engineered microfluidic platform incorporating engineered beads to reduce nonspecific binding, electrostatic bead–microwell pairing for improved capture efficiency, and an algorithmic calibration model to extend the dynamic range. These innovations collectively improve the analytical sensitivity and quantification accuracy for plasma Aβ1–42 and pTau181. Statistical analyses assessed correlation between our microfluidic platform and Quanterix Simoa, and evaluated our diagnostic ability using the Quanterix Simoa measurements as the reference standard in individuals with AD (N = 107) and cognitively normal controls (N = 100). We further validated diagnostic cutoff values in an independent cohort. The microfluidic platform demonstrates a superior diagnostic performance and enables reliable longitudinal monitoring of plasma biomarkers. Our results highlight the potential of the surface-engineered microfluidic platform for clinical translation in neurodegenerative disease diagnostics.
研究领域:
神经退行性疾病
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生物医学工程
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微流控技术
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生物标志物检测
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临床诊断
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产品关联
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PubMed
高影响因子
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
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2021
·
IF 5.051
Chengyao Wu,Guijuan Zhang,Zai-Wei Zhang,Xia Jiang,Ziwen Zhang,Huanhuan Li,Hua-Li Qin,Wenjian Tang
To discover novel scaffolds as leads against dementia, a series of δ-aryl-1,3-dienesulfonyl fluorides with α-halo, α-aryl and α-alkynyl were assayed for ChE inhibitory activity, in which compound A10 was identified as a selective BuChE inhibitor (IC50 = 0.021 μM for eqBChE, 3.62 μM for hBuChE). SAR of BuChE inhibition showed: (i) o- > m- > p-; –OCH3 > –CH3 > –Cl (–Br) for δ-aryl; (ii) α-Br > α-Cl, α-I. Compound A10 exhibited neuroprotective, BBB penetration, mixed competitive inhibitory effect on BuChE (Ki = 29 nM), and benign neural and hepatic safety. Treatment with A10 could almost entirely recover the Aβ1-42-induced cognitive dysfunction to the normal level, and the assessment of total amount of Aβ1-42 confirmed its anti-amyloidogenic profile. Therefore, the potential BuChE inhibitor A10 is a promising effective lead for the treatment of AD.
研究领域:
神经科学
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药理学
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药物化学
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高影响因子
JOURNAL OF CELLULAR PHYSIOLOGY
·
2019
·Vol. 234
·期 12
·21860-21876
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IF 4.522
Kaimin Wu,Ruiyi Zhang,Yanhui Lu,Lulu Wen,Yanfei Li,Ranran Duan,Yaobing Yao,Yanjie Jia
Mesenchymal stem cells (MSCs) transplantation has emerged as a potential therapeutic approach for Alzheimer's disease (AD). However, the poor proliferation capacity and low survival rate of engrafted MSCs in the hostile microenvironment of AD limit their therapeutic efficiency. Lin28B is a conserved RNA-binding protein associated with cell self-renewal and survival. The purpose of the present study was to explore whether lin28B might influence the functions of implanted MSCs and strengthen their neuroprotective potential in AD. A gain-of-function assay was used to upregulate lin28B expression in MSCs by lentiviral transfection. Our in vitro results indicated that lin28B promoted MSCs proliferation and migration, and protected MSCs against Aβ1–42-induced cell death by upregulating insulin-like growth factor-2 (IGF-2). Blockage of IGF-2 partially abrogated the above effects of lin28B. After intracerebroventricular injection into amyloid precursor protein/presenilin 1 mice, implanted MSCs were monitored using bioluminescence imaging. We observed that administration of MSCs transfected with lin28B significantly stimulated their proliferation and prolonged cell retention after delivery. Moreover, administration of the transfected MSCs markedly mitigated cognitive deficits, promoted amyloid plaque clearance, decreased the activation of microglia, and reduced neuronal cell death. The data above confirmed our hypothesis that lin28B is a crucial modulator determining the fate of transplanted MSCs by regulating IGF-2-associated pathways and thereby enhancing their protective effects against AD.
研究领域:
神经科学
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干细胞生物学
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分子生物学
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神经退行性疾病
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PubMed
高影响因子
Frontiers in Aging Neuroscience
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2024
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IF 4.1
Xue Weikang,Lei Ziyi,Liu Bin,Guo Hanxin,Yan Weiyi,Jin Youngnam N.,Yu Yanxun V.
Neurodegenerative diseases such as Alzheimer's disease and polyglutamine diseases are characterized by abnormal accumulation of misfolded proteins, leading to neuronal dysfunction and subsequent neuron death. However, there is a lack of studies that integrate molecular, morphological, and functional analyses in neurodegenerative models to fully characterize these time-dependent processes. In this study, we used C. elegans models expressing Aβ1-42 and polyglutamine to investigate early neuronal pathogenic features in olfactory neurons. Both models demonstrated significant reductions in odor sensitivity in AWB and AWC chemosensory neurons as early as day 1 of adulthood, while AWA chemosensory neurons showed no such decline, suggesting cell-type-specific early neuronal dysfunction. At the molecular level, Aβ1-42 or Q40 expression caused age-dependent protein aggregation and morphological changes in neurons. By day 6, both models displayed prominent protein aggregates in neuronal cell bodies and neurites. Notably, AWB neurons in both models showed significantly shortened cilia and increased instances of enlarged cilia as early as day 1 of adulthood. Furthermore, AWC neurons expressing Aβ1-42 displayed calcium signaling defects, with significantly reduced responses to odor stimuli on day 1, further supporting early behavioral dysfunction. In contrast, AWA neuron did not exhibit reduced calcium responses, consistent with the absence of detectable decreases in olfactory sensitivity in these neurons. These findings suggest that decreased calcium signaling and dysfunction in specific sensory neuron subtypes are early indicators of neurodegeneration in C. elegans, occurring prior to the formation of visible protein aggregates. We found that the ER unfolded protein response (UPR) is significantly activated in worms expressing Aβ1-42. Activation of the AMPK pathway alleviates olfactory defects and reduces fibrillar Aβ in these worms. This study underscores the use of C. elegans olfactory neurons as a model to elucidate mechanisms of proteostasis in neurodegenerative diseases and highlights the importance of integrated approaches.
研究领域:
神经科学
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分子生物学
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神经退行性疾病
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模式生物
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PubMed
高影响因子
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