CNS Neuroscience & Therapeutics
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2023
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IF 5.5
Tao Zhang,Yuan Tian,Xiaoqing Zheng,Ruomeng Li,Li Hu,Xindong Shui,Yingxue Mei,Quling Wang,Mi Zhang,Xiuzhi Zheng,Long Wang,Dongmei Chen,Wucheng Tao,Tae Ho Lee
Aims The autophagy-lysosomal pathway is important for maintaining cellular proteostasis, while dysfunction of this pathway has been suggested to drive the aberrant intraneuronal accumulation of tau protein, leading to synaptic damage and cognitive impairment. Previous studies have demonstrated that the activation of transient receptor potential vanilloid 1 (TRPV1) by capsaicin has a positive impact on cognition and AD-related biomarkers. However, the effect and mechanism of TPRV1 activation on neuronal tau homeostasis remain elusive. Methods A mouse model of tauopathy was established by overexpressing full-length human tau in the CA3 area. Mice were fed capsaicin diet (0.0125%) or normal diet for 9 weeks. The cognitive ability, synaptic function, tau phosphorylation levels, and autophagy markers were detected. In vitro, capsaicin-induced alterations in cellular autophagy and tau degradation were characterized using two cell models. Besides, various inhibitors were applied to validate the role of TRPV1-mediated autophagy enhancement in tau clearance. Results We observed that TRPV1 activation by capsaicin effectively mitigates hippocampal tau accumulation-induced synaptic damages, gliosis, and cognitive impairment in vivo. Capsaicin promotes the degradation of abnormally accumulated tau through enhancing autophagic function in neurons, which is dependent on TRPV1-mediated activation of AMP-activated protein kinase (AMPK) and subsequent inhibition of the mammalian target of rapamycin (mTOR). Blocking AMPK activation abolishes capsaicin-induced autophagy enhancement and tau degradation in neurons. Conclusion Our findings reveal that capsaicin-induced TRPV1 activation confers neuroprotection by restoring neuronal tau homeostasis via modulating cellular autophagy and provides additional evidence to support the potential of TRPV1 as a therapeutic target for tauopathies.
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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DOI
PubMed
高影响因子
ANALYTICAL AND BIOANALYTICAL CHEMISTRY
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2019
·Vol. 411
·期 20
·5277-5285
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IF 3.286
Chen Li,Lin Jianwei,Yi Jinquan,Weng Qinghua,Zhou Ying,Han Zhizhong,Li Chunyan,Chen Jinghua,Zhang Qian
Rapid, highly sensitive detection of tau protein and other neurodegenerative biomarkers remains a significant hurdle for diagnostic tests for Alzheimer's disease. In this work, we developed a novel tyrosinase (TYR)-induced tau aptamer–tau–tau antibody (anti-tau) sandwich fluorescence immunoassay to detect tau protein that used dopamine (DA)-functionalized CuInS 2 /ZnS quantum dots as the fluorophore. CuInS 2 /ZnS core/shell quantum dots with high luminescence, low toxicity, and excellent biocompatibility were successfully fabricated and decorated with DA through amide conjugation. Meanwhile, TYR was conjugated with anti-tau by a click reaction. When DA-functionalized CuInS 2 /ZnS quantum dots were added to the sandwich system, TYR catalyzed the transformation of DA to dopamine quinone, which acted as an effective electron acceptor and triggered fluorescence quenching. The fluorescence intensity of the immunoassay based on DA-functionalized CuInS 2 /ZnS quantum dots shows good performance in terms of linearity with the logarithm of tau protein concentration, with a linear concentration range from 10 pM to 200 nM. This work is the first to use a TYR-induced fluorescence immunoassay for the rapid detection of tau protein, paving a new way for the detection of disease biomarkers.
Graphical abstract
研究领域:
生物化学
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纳米技术
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神经科学
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诊断学
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DOI
PubMed
高影响因子
Frontiers in Aging Neuroscience
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2022
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IF 5.702
Yang Xiao-bo,Zu Heng-bing,Zhao Yong-fei,Yao Kai
Agomelatine, an agonist of melatonergic MT1 and MT2 receptors and a selective 5-hydroxytryptamine 2C receptor antagonist, is widely applied in treating depression and insomnia symptoms in several neurogenerative diseases. However, the neuroprotective effect of agomelatine in Alzheimer’s disease (AD) is less known. In this study, a total of 30 mice were randomly divided into three groups, namely, wild type (WT), APP/PS1, and agomelatine (50 mg/kg). After 30 days, the Morris water maze was performed to test the cognitive ability of mice. Then, all mice were sacrificed, and the hippocampus tissues were collected for ELISA, Western blot, and immunofluorescence analysis. In this study, we found that agomelatine attenuated spatial memory deficit, amyloid-β (Aβ) deposition, tau phosphorylation, and neuroinflammation in the hippocampus of APP/PS1 mice. Further study demonstrated that agomelatine treatment upregulated the protein expression of DHCR24 and downregulated P-Akt, P-mTOR, p-p70s6k, Hes1, and Notch1 expression. In summary, our results identified that agomelatine could improve cognitive impairment and ameliorate AD-like pathology in APP/PS1 mice via activating DHCR24 signaling and inhibiting Akt/mTOR and Hes1/Notch1 signaling pathway. Agomelatine may become a promising drug candidate in the therapy of 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
Journal of Advanced Research
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2025
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IF 13
Ruomeng Li,Xueyin Wu,Jing Yao,Jiawen Chen,Xindong Shui,Xiaoqing Zheng,Wujin Tian,Long Wang,Ying Zhou,Tao Zhang,Dongmei Chen,Yang Liu,Tae Ho Lee
Introduction The upregulation of death-associated protein kinase 1 (DAPK1) is involved in tau hyperphosphorylation, neuronal apoptosis and cognitive dysfunction, which are key pathological features of Alzheimer’s disease (AD). This result suggests that DAPK1 is novel therapeutic target for AD. Objectives This study aimed to evaluate the efficacy and mechanism of action of CJ1, a novel hydrophobic tagging (HyT)-based degrader, in targeting DAPK1 and alleviating in AD. Methods A library of HyT-based bifunctional molecules was synthesized and systematically screened for their ability to degrade DAPK1 in vitro . CJ1 emerged as the most potent candidate degrader of DAPK1, and its capacity to induce DAPK1 degradation via the proteasome system was further evaluated. Its effects on tau phosphorylation and neuronal viability were evaluated in multiple cellular models. The in vivo efficacy of systemic CJ1 administration was assessed in two tau-related pathology (tauopathy) mouse models, AAV-hTau-P301L and hTau transgenic mice. Behavioral, biochemical, and histological analyses were performed to evaluate cognitive function, tau pathology, neuroinflammation, neurodegeneration, and safety. Results CJ1 selectively promoted the posttranslational degradation of DAPK1 by the proteasome system without affecting DAPK1 mRNA expression. In vitro studies demonstrated that CJ1 significantly reduced tau phosphorylation at multiple AD-related sites. In vivo , CJ1 effectively penetrated the BBB, decreased the levels of both the soluble and insoluble forms of hyperphosphorylated tau, and suppressed the formation of neurofibrillary tangles. Additionally, CJ1 treatment restored synaptic and dendritic structures, enhanced spatial learning and memory, attenuated neuroinflammatory responses, preserved neuronal populations, and produced no evidence of systemic toxicity. Conclusion CJ1 functions as a potent and selective degrader of DAPK1, exerting neuroprotective effects by reducing tau hyperphosphorylation and preserving neuronal structural integrity. These findings support DAPK1 as a promising therapeutic target and suggest that further preclinical studies are warranted to evaluate CJ1 as a potential treatment for tauopathies associated with AD.
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PubMed
高影响因子
ZOOLOGICAL RESEARCH
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2024
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IF 4
Na Zhao,Xiu Chen,Qiu-Gu Chen,Xue-Ting Liu,Fan Geng,Meng-Meng Zhu,Fu-Ling Yan,Zhi-Jun Zhang,Qing-Guo Ren
Emerging evidence indicates that sleep deprivation (SD) can lead to Alzheimer’s disease (AD)-related pathological changes and cognitive decline. However, the underlying mechanisms remain obscure. In the present study, we identified the existence of a microbiota-gut-brain axis in cognitive deficits resulting from chronic SD and revealed a potential pathway by which gut microbiota affects cognitive functioning in chronic SD. Our findings demonstrated that chronic SD in mice not only led to cognitive decline but also induced gut microbiota dysbiosis, elevated NLRP3 inflammasome expression, GSK-3β activation, autophagy dysfunction, and tau hyperphosphorylation in the hippocampus. Colonization with the “SD microbiota” replicated the pathological and behavioral abnormalities observed in chronic sleep-deprived mice. Remarkably, both the deletion of NLRP3 in NLRP3 -/- mice and specific knockdown of NLRP3 in the hippocampus restored autophagic flux, suppressed tau hyperphosphorylation, and ameliorated cognitive deficits induced by chronic SD, while GSK-3β activity was not regulated by the NLRP3 inflammasome in chronic SD. Notably, deletion of NLRP3 reversed NLRP3 inflammasome activation, autophagy deficits, and tau hyperphosphorylation induced by GSK-3β activation in primary hippocampal neurons, suggesting that GSK-3β, as a regulator of NLRP3-mediated autophagy dysfunction, plays a significant role in promoting tau hyperphosphorylation. Thus, gut microbiota dysbiosis was identified as a contributor to chronic SD-induced tau pathology via NLRP3-mediated autophagy dysfunction, ultimately leading to cognitive deficits. Overall, these findings highlight GSK-3β as a regulator of NLRP3-mediated autophagy dysfunction, playing a critical role in promoting tau hyperphosphorylation.
研究领域:
神经科学
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微生物学
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病理学
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认知科学
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DOI
PubMed
高影响因子
PSYCHOPHARMACOLOGY
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2022
·Vol. 239
·期 11
·3579-3593
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IF 4.415
Mou Chen-Ye,Xie Yan-Fei,Wei Jia-Xin,Wang Qi-Yao,Le Jing-Yang,Bao Yong-Jie,Zhang Pan-Pan,Mao Yue-Chun,Huang Xing-Han,Pan Han-Bo,Naman C. Benjamin,Liu Lin,Liang Hong-Ze,Wu Xiang,Xu Jia,Cui Wei
Rationale
Tau hyperphosphorylation and aggregation is considered as a main pathological mechanism underlying Alzheimer’s disease (AD). Rose Bengal (RB) is a synthetic dye used for disease diagnosis, which was reported to inhibit tau toxicity via inhibiting tau aggregation in Drosophila . However, it was unknown if RB could produce anti-AD effects in rodents. Objectives The research aimed to investigate if and how RB could prevent β-amyloid (Aβ) oligomers-induced tau hyperphosphorylation in rodents. Methods and results RB was tested in vitro (0.3–1 μM) and prevented Aβ oligomers-induced tau hyperphosphorylation in PC12 cells. Moreover, RB (10–30 mg/kg, i.p. ) effectively attenuated cognitive impairments induced by Aβ oligomers in mice. Western blotting analysis demonstrated that RB significantly increased the expression of pSer473-Akt, pSer9-glycogen synthase kinase-3β (GSK3β) and reduced the expression of cyclin-dependent kinase 5 (CDK5) both in vitro and in vivo. Molecular docking analysis suggested that RB might directly interact with GSK3β and CDK5 by acting on ATP binding sites. Gene Ontology enrichment analysis indicated that RB might act on protein phosphorylation pathways to inhibit tau hyperphosphorylation. Conclusions RB was shown to inhibit tau neurotoxicity at least partially via inhibiting the activity of GSK3β and CDK5, which is a novel neuroprotective mechanism besides the inhibition of tau aggregation. As tau hyperphosphorylation is an important target for AD therapy, this study also provided support for investigating the drug repurposing of RB as an anti-AD drug candidate.
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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病理学
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产品关联
DOI
PubMed
高影响因子
ACS Chemical Neuroscience
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2021
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IF 4.418
Yuan Hu,Danjing Yang,Ying Tu,Keke Chai,Lei Chu,Shuo Shi,Tianming Yao
A molecular inhibitor of tau protein aggregation offers an attractive therapeutic possibility as disease-modifying treatment of Alzheimer’s disease. However, the ineffectiveness as well as adjoint toxicity due to superficial understanding of the inhibition mechanism has hindered drug development. Conventional approaches for screening drug ligands rely on compatible docking with the well-defined structure of a protein receptor. Therefore, the design of tau aggregation inhibitors has been inevitably hindered by the unstructured, highly dynamic nature of the tau protein. This paper suggested a new strategy for reducing tau aggregation through a dynamic process of conformational isomerization. A group of glucose gallate derivatives were selected as tau aggregation inhibitors. These star-shaped molecules have a biocompatible glucose core surrounded by several gallic acid polyphenol arms, which can bind to peptide chains at different sites, probably through hydrogen bonds and π–π stacking. Theoretically, by elevating the saddle point on the potential energy surfaces (PES) of proteins, the barrier in the dynamic pathway of peptide isomerization, glucose gallates effectively inhibit tau aggregation through a dynamic mechanism. A tau cell model based on human neurons was constructed. For the first time, we confirmed that the moderate thermodynamic binding of the molecular ligand to the tau peptide chain can not only prevent the isomerization of the peptide chain leading to aggregation but also avoid toxicity resulting from the dissociation of tau from microtubules.
研究领域:
神经科学
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药物化学
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分子生物学
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DOI
PubMed
高影响因子
Scientific Reports
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2023
·Vol. 13
·期 1
·1-13
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IF 4.6
Chakari-Khiavi Forough,Mirzaie Arezoo,Khalilzadeh Balal,Yousefi Hadi,Abolhasan Rozita,Kamrani Amin,Pourakbari Ramin,Shahpasand Koorosh,Yousefi Mehdi,Rashidi Mohammad-Reza
Alzheimer’s disease (AD) is a progressive brain disorder characterized by the ongoing decline of brain functions. Studies have revealed the detrimental effects of hyperphosphorylated tau (p-tau) protein fibrils in AD pathogenesis, highlighting the importance of this factor in the early-stage detection of AD conditions. We designed an electrochemical immunosensor for quantitative detection of the cis conformation of the p-tau protein ( cis -p-tau) employing platinum nanoparticles (Pt NPs) supported on zeolitic imidazolate frameworks (ZIF) for modifying the glassy carbon electrode (GCE) surface. Under optimum conditions, the immunosensor selectively and sensitively detected cis-p-tau within the broad linear range of 1 fg mL −1 to 10 ng mL −1 and the low limit of detection (LOD) of 1 fg mL −1 with desired reproducibility and stability. Furthermore, the fabricated immunosensor's performance was examined for the cis-p-tau analysis in the serum of AD patients, indicating its accuracy and feasibility for real-sample analysis. Notably, this is the first application of Pt@ZIF-8 nanocomposite in fabricating a valid immunosensor for selective cis-p-tau detection, even in the presence of trans-p-tau. It is worth mentioning that the enzyme-linked immunosorbent assay (ELISA) reference technique is not able to evaluate pico- or femtomolar concentrations of cis-p-tau, making the fabricated immunosensor superior for early-stage measurement and screening of AD.
研究领域:
医学诊断
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生物传感技术
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神经科学
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PubMed
高影响因子
SENSORS AND ACTUATORS B-CHEMICAL
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2022
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IF 9.221
Zhao-huan Zhang,Junjie Hu,Han Zhu,Qiang Chen,Kwangnak Koh,Hongxia Chen,Xiao-hui Xu
Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative disease. Plasma total phosphorylated tau (P-tau) with multi-phosphorylation sites is a potentially efficient biomarker for the diagnosis and prognosis of AD. Single phosphorylation site recognition methods lead to the false positive detection of P-tau and decrease the accuracy of AD analysis. In this work, a simple and precise electrochemical immunoassay was developed for the specific detection of P-tau. Calixarene derivative ProLinker was utilized to orient Anti-tau onto the surface of gold electrode. ProLinker provide abundant binding sites for immobilized antibodies via host-guest recognitions and ensure Anti-tau activity through non-covalent interactions. Flower-shaped TiO 2 (F-TiO 2 ) forming coordination bonds with the phosphate group of phosphorylated protein were utilized as signal amplification tags to construct a simple sandwich assay for multiple phosphorylated sites sensing of P-tau. The combination of F-TiO 2 and Anti-tau ensured the bispecific and precise recognition of P-tau with a wide detection range (1–200 ng/mL) and a low detection of limit (1.774 pg/mL). With large specific surface area, high electron hinder ability, and great stability, F-TiO 2 as an amplification molecule can improve the performance of the immunosensor and produce sensitive signal changes according to the concentration of P-tau in the clinical samples. Hence, this P-tau immunoassay paves the way for the development of efficient detection tools for clinical diagnosis and monitoring.
研究领域:
生物医学工程
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神经科学
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诊断学
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产品关联
DOI
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2022
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IF 3.322
Yanwen Wang,Miao Cai,Yue Lou,Siran Zhang,Xiaoli Liu
To elucidate the potential molecular mechanisms of ZBTB20-AS1 on ZBTB20 and GSK-3β/Tau signaling pathway in the pathogenesis of Alzheimer's disease (AD), SH-SY5Y cells were obtained for in vitro experiments and AD models were constructed using β-Amyloid 1–42. CCK8 assay was implemented for determining cell viability . Flow cytometry was used for cell apoptosis detection. Dual-luciferase reporter and RNA-RNA pull down assay was employed for elucidating molecular interactions . Immunohistochemistry, RT-qPCR and western blotting were performed for measuring gene expression. The results showed that expression of LncRNA ZBTB20-AS1 was significantly upregulated, while ZBTB20 was downregulated in SH-SY5Y-AD cells. ZBTB20 was the target gene of LncRNA ZBTB20-AS1. Overexpression of ZBTB20 or knockdown of LncRNA ZBTB20-AS1 inhibited SH-SY5Y-AD cells apoptosis and suppressed GSK3β/Tau pathway, and knockdown of ZBTB20-AS1 increased cell viability and decreased apoptosis. In conclusion, overexpression of ZBTB20-AS1 inhibited ZBTB20 expression and promoted GSK-3β expression and Tau phosphorylation, contributing to the development of AD.
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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病理学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
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2018
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IF 8.097
Mengmeng Xu,Hui Zhou,Yanan Liu,Jing Sun,Wenjie Xie,Ping Zhao,Jie Liu
Alzheimer’s disease (AD) has become one of the most serious societal problems globally, with no effective treatments. Parenchymal accumulation of amyloid beta (Aβ) plaques and the formation of neurofibrillary tangles are the hallmarks of AD. Their possible interactions and synergistic effects in AD have been gradually elucidated. The failure of many clinical trials suggests that it is difficult to treat AD with a focus on a single target. Instead, multiple targets may be an important direction for AD drug research. In this study, we used protoporphyrin IX (PX)-modified oxidized mesoporous carbon nanospheres (OMCN) (PX@OMCN@PEG(OP)@RVGs) as a novel AD multifunctional nanodrug having multiple targets. The nanodrug efficiently inhibits tau phosphorylation. In addition, the use of PX with focused ultrasound triggered the production of reactive oxygen species that significantly inhibited Aβ aggregation. Both approaches notably increased the cognitive level of APP/PS1 transgenic (Tg) mice and ultimately achieved dual-target inhibition of AD. Furthermore, the safe and effective delivery of PX across the blood–brain barrier (BBB) due to modification of the RVG peptide was demonstrated in vivo and in vitro. The favorable photothermal effect of the nanoparticles improved the BBB permeability of PX@OP@RVGs under near-infrared irradiation. The results demonstrated that the novel PX@OP@RVG multifunctional nanomedicine has a dual-target treatment capability for AD and can traverse the BBB, indicating the potential for the effective treatment of AD.
研究领域:
神经科学
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药物递送
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
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2020
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IF 3.209
Xu Hun,Xiaohui Kong
Alzheimer’s disease is a worldwide health problem and it has attracted extensive attention. Tau protein is an important biomarker in the pathogenesis of Alzheimer’s disease. Herein, we devise a in situ enzyme catalysis generating electron donor photoelectrochemical (PEC) biosensor for Tau-381 protein. Tau-381 protein aptamer is immobilized onto the surface of AuNPs/MoSe 2 nanosheets modified electrode. In the presence of Tau-381 protein, an aptamer-protein duplex is formed. Meanwhile, the Tau-381 antibody and the protein G/AP (protein G labeled with alkaline phosphatase) are captured with the affinity interaction between Tau-381 protein and Tau-381 antibody, Tau-381 antibody and protein G/AP. The electron donor, ascorbic acid, is in situ produced by the catalyzing of ascorbic acid 2-phosphate in the PEC detection solution. As a result, low blank noise and strong photocurrent response are engendered. The photocurrent response is related to the concentration of Tau-381 protein. The detection range of Tau-381 protein is from 0.5 fM to 1.0 nM with detection limit of 0.3 fM. This in situ generating electron donor PEC biosensor can detect various targets by simply alternating antibody, antigen, or aptamer commercially. Thus, this work represents a simple and general sensing protocol.
研究领域:
生物传感器
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神经退行性疾病
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分析化学
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纳米技术
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光电化学
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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）