INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2023
·
IF 8.2
Huan-Huan Yin,Yin-Lei Han,Xiao Yan,Yi-Xin Guan
Alzheimer's disease (AD) is one of the most serious neurodegenerative diseases with no effective treatment options available. The formation of insoluble amyloid fibrils of the hyperphosphorylated tau protein is intimately associated with AD, hence the tau protein has been a key target for AD drug development. In this work, hematoxylin was discovered as a dual functional compound, that is, acting in the inhibition of repeat domain of tau (tau-RD) protein fibrillogenesis and remodeling of pre-formed tau-RD fibrils in vitro . Meanwhile, hematoxylin was able to reduce the accumulation of tau-RD aggregates in Saccharomyces cerevisiae . Experimental and computational studies indicated that hematoxylin directly interacts with tau-RD protein through hydrophobic forces, hydrogen bonds, π -cation interactions, and π - π stackings. In addition, cellular viability assays showed that hematoxylin greatly reduced cytotoxicity induced by tau-RD aggregates. In summary, hematoxylin might be a promising candidate for further development as a potential therapeutic drug for AD patients.
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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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2021
·
IF 6.953
Shifeng Xiao,Yafei Lu,Qiuping Wu,Jiaying Yang,Jierui Chen,Suyue Zhong,David Eliezer,Qiulong Tan,Chengchen Wu
Alzheimer's disease is a neurodegenerative disease which severely impacts the health of the elderly. Current treatments are only able to alleviate symptoms, but not prevent or cure the disease. The neurofibrillary tangles formed by tau protein aggregation are one of the defining characteristics of Alzheimer's disease, so tau protein has become a key target for the drug design. In this study, we show that fisetin, a plant-derived polyphenol compound, can inhibit aggregation of the tau fragment, K18, and can disaggregate tau K18 filaments in vitro . Meanwhile it is able to prevent the formation of tau aggregates in cells. Both experimental and computational studies indicate that fisetin could directly interact with tau K18 protein. The binding is mainly created by hydrogen bond and van der Waal force, prevents the formation of β-strands at the two hexapeptide motifs, and does not perturb the secondary structure or the tubulin binding ability of tau protein. In summary, fisetin might be a candidate for further development as a potential preventive or therapeutic drug for Alzheimer's disease.
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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生物化学
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产品关联
DOI
PubMed
高影响因子
ACS Chemical Neuroscience
·
2020
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IF 4.486
Yuan Hu,Xiaochun Hu,Yonglin Lu,Shuo Shi,Danjing Yang,Tianming Yao
Inhibition of Tau protein aggregation is an attractive therapeutic target for Alzheimer’s disease. However, most of the inhibitors have failed in clinical trials due to the superficial understanding of inhibition mechanism and drug-transfer pharmacokinetics. Innovation of design strategy has become a top priority. To afford a hairpinlike molecular inhibitor, we introduced tannic acid, a multibranched polyphenol molecule, and its moiety, gallic acid. We showed that tannic acid could effectively inhibit Tau aggregation through a multidentate chelation mode. We then encapsulated tannic acid in a non-neurotoxic liposome by lecithin/β-sitosterol, overcoating with Tween 80. Using transwell devices, we cytologically demonstrated that tannic acid liposome can successfully be transferred across the model of a blood–brain barrier made up of mouse brain microvascular endothelial cell bEnd.3 and effectively reduce Tau aggregation induced by fibrils of Tau peptide R3 in human neuroblastoma cell SK-N-SH. This result indicates the potential therapeutic effect of tannic acid liposome on Alzheimer’s disease.
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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药物递送系统
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产品关联
DOI
PubMed
高影响因子
DRUG DELIVERY
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2020
·
IF 4.902
Yao Qi,Lin Guo,Yibing Jiang,Yijie Shi,Haijuan Sui,Liang Zhao
It is reported that quercetin (Que) can prevent tau pathology and induce neuroprotection by improving cognitive and functional symptoms in the treatment of Alzheimer’s disease (AD). However, its clinical application has been limited due to its poor brain targeting and bioavailability. Exosomes are considered as cargo carriers for intercellular communication and especially serve as a natural and important drug brain delivery platform for achieving better treatment of central neurological diseases. Here, we developed plasma exosomes (Exo) loaded with Que (Exo-Que) to improve the drug bioavailability, enhance the brain targeting of Que and potently ameliorate cognitive dysfunction in okadaic acid (OA)-induced AD mice. Our results showed that Exo-Que improved brain targeting of Que as well as significantly enhanced bioavailability of Que. Furthermore, compared with free Que, Exo-Que better relieved the symptoms of AD by inhibiting cyclin-dependent kinase 5 (CDK5)-mediated phosphorylation of Tau and reducing formation of insoluble neurofibrillary tangles (NFTs), suggesting its therapeutic potential for better treatment of AD.
研究领域:
神经科学
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药理学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
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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产品关联
DOI
PubMed
高影响因子
Experimental and Therapeutic Medicine
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2018
·Vol. 16
·期 6
·4951-4958
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IF 1.41
Lili Zhong,Hong Liu,Weijia Zhang,Xu Liu,Bo Jiang,Hongxin Fei,Zhongren Sun
β‑amyloid (Aβ) aggregation and tau hyperphosphorylation are considered to be the primary pathological hallmarks of Alzheimer's disease (AD). Targeted inhibition of these pathological processes may provide effective treatments for AD. Accumulating evidence has demonstrated that ellagic acid (EA) exerts neuroprotective effects in several diseases. The present study investigated the effects of EA on AD‑associated learning and memory deficits on APP/PS1 double transgenic mice and the underlying mechanisms. APP/PS1 mice or wild‑type C57BL/6 mice were intragastrically administered EA (50 mg/kg/day) or vehicle for 60 consecutive days. The learning and memory abilities of mice were investigated using the Morris water maze test. Hippocampal regions were examined for the presence of amyloid plaques, neuronal apoptosis and tau phosphorylation. Expression levels of APP, Aβ, RAC‑αserine/threonine‑protein kinase and glycogen synthase kinase (GSK)3β in the hippocampus were determined by western blot analysis and ELISA. The results demonstrated that EA treatment ameliorated spatial learning and memory impairment in APP/PS1 mice and significantly reduced neuronal apoptosis and Aβ deposition in the hippocampus (P<0.05 and P<0.01). In addition, EA significantly inhibited the hyperphosphorylation of tau and significantly decreased the activity of glycogen synthase kinase (GSK)3β (P<0.01), which is involved in tau phosphorylation. Overall, these findings indicated that the beneficial effects of EA on AD‑associated cognitive impairments may be attributed to the inhibition of Aβ production and tau hyperphosphorylation, and its beneficial action may be mediated in part, by the RAC‑α serine/threonine‑protein kinase/GSK3β signaling 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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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
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2017
·Vol. 41
·期 2
·1138-1146
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IF 2.341
Xiu‑Yin Shen,Tao Luo,Sheng Li,Ou‑Yang Ting,Feng He,Jie Xu,Hua‑Qiao Wang
Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by aberrant tau protein hyperphosphorylation, which eventually leads to the formation of neurofibrillary tangles. Hyperphosphorylated tau protein is considered as a vital factor in the development of AD and is highly associated with cognitive impairment. Therefore, it is recognized to be a potential therapeutic target. Quercetin (QUE) is a naturally occurring flavonoid compound. In the present study, the inhibitory effect of QUE on okadaic acid (OA)-induced tau protein hyperphosphorylation in HT22 cells was explored. Western blotting results indicated that QUE significantly attenuated OA‑induced tau protein hyperphosphorylation at the Ser396, Ser199, Thr231 and Thr205 sites. Further experiments demonstrated that QUE inhibited the activity of cyclin‑dependent kinase 5 (CDK5), a key enzyme in the regulation of tau protein, and blocked the Ca2+‑calpain‑p25‑CDK5 signaling pathway. These observations indicate the ability of QUE to decrease tau protein hyperphosphorylation and thereby attenuate the associated neuropathology. In conclusion, these results support the potential of QUE as a therapeutic agent for AD and other neurodegenerative 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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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
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2020
·
IF 10.317
Hui Zhou,Youcong Gong,Yanan Liu,Anlian Huang,Xufeng Zhu,Jiawei Liu,Guanglong Yuan,Li Zhang,Ji-an Wei,Jie Liu
Alzheimer's disease (AD) seriously affects human health and life and lacks effective treatments. The lessons of many clinical trial failures suggest that targeting amyloid beta to treat AD is difficult, and finding new targets is an important direction for AD drug research. The neurofibrillary tangles formed by hyperphosphorylation of tau protein induce the production of cytotoxic reactive oxygen species (ROS) and cause neuronal apoptosis . Therefore, inhibition of hyperphosphorylation of tau protein and reduction of neuronal damage have become promising methods for the treatment of AD. We herein designed a novel nanocomposite with high stability and good biocompatibility by using flower-shaped hollow nano-ruthenium (Ru NPs) as a carrier, loading nerve growth factor (NGF) and sealing with phase change material (PCM). Due to its excellent photothermal effect, under the near-infrared (NIR) irradiation, the nanocomposite could effectively penetrate the blood-brain barrier (BBB) and respond to phase changes in the lesion area, releasing NGF, which inhibited tau hyperphosphorylation, reduced oxidative stress , and more importantly restored nerve damage and maintained neuronal morphology, thereby significantly improving learning and memory in AD mice. Thus, the experimental results indicate that multifunctional nanocomposites may be a promising drug in the treatment of AD.
研究领域:
神经科学
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药理学
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纳米医学
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DOI
PubMed
高影响因子
Theranostics
·
2024
·Vol. 14
·期 16
·6218
·
IF 12.4
Yutian Gu,Qin Zhang,Honglin Huang,Kwun Hei Willis Ho,Yu Zhang,Changqing Yi,Yifan Zheng,Raymond Chuen Chung Chang,Emma Shujun Wang,Mo Yang
Rationale: Alzheimer's disease (AD) is hallmarked by amyloid-β (Aβ) plaques and hyperphosphorylated tau (p-tau) neurofibrillary tangles. While Aβ-centric therapies have shown promise, the complex pathology of AD requires a multifaceted therapeutic approach. The weak association between Aβ levels and cognitive decline highlights the need for alternative theranostic strategies. Currently, oxidative stress and tau hyperphosphorylation are now recognized as critical pathological events in AD. Thus, therapies that concurrently attenuate oxidative stress damage and inhibit tau pathology hold great potential for AD treatment. Methods: Herein, a multifunctional neuron-targeted nanocomposite is devised to realize dual imaging-guided AD therapy, integrating the inhibition of tau pathology and reactive oxygen species (ROS)-neutralizing biofunctions. The construction of the nanocomposite incorporates polyphenolic antioxidants tannic acid (TA)-based nanoparticles carrying manganese ions (Mn 2+ ) and fluorescent dye IR780 iodide (IR780), coupled with a neuron-specific TPL peptide. The resulting IR780-Mn@TA-TPL nanoparticles (NPs) are comprehensively evaluated in both in vitro and in vivo AD models to assess their imaging capabilities and therapeutic efficacy. Results: The nanocomposite facilitates Mn-enhanced magnetic resonance (MR) imaging and near-infrared (NIR) fluorescence imaging. It effectively neutralizes toxic ROS and reduces tau hyperphosphorylation and aggregation. In AD rat models, the nanocomposite restores neuronal density in the hippocampus and significantly improves spatial memory. Conclusions: Such a neuron‑targeting multifunctional nanocomposite represents a potential theranostic strategy for AD, signifying a shift towards bimodal imaging-guided treatment approaches.
研究领域:
神经科学
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药学
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纳米技术
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医学影像
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DOI
PubMed
高影响因子
PHYSIOLOGY & BEHAVIOR
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2023
·
IF 2.9
Bo Pang,Lu-Lu Zhang,Bin Li,Feng-Xian Sun,Zhi-Da Wang
An antidiabetic agent sodium glucose co-transporter 2 (SGLT2) inhibitor ertugliflozin has been revealed to bind to catalytic anionic site of acetylcholinesterase (AChE), which is considered to be associated with the cognitive decline in neurodegenerative diseases, such as Alzheimer's disease (AD). The aim of the present study was thus to probe the effect of ertugliflozin on AD. Intracerebroventricular injection of streptozotocin (STZ/i.c.v) (3 mg/kg) was done bilaterally in male Wistar rats at 7–8 weeks of age. Two treatment doses (5 mg/kg and 10 mg/kg) of ertugliflozin were given intragastrically to STZ/i.c.v-induced rats for 20 days daily for behavioral assessment. Biochemical estimations of cholinergic activity, neuronal apoptosis, mitochondrial function and synaptic plasticity were performed. Behavioral results with ertugliflozin treatment revealed attenuation of cognitive deficit. Ertugliflozin also inhibited hippocampal AChE activity, downregulated pro-apoptotic marker expression, as well as mitigated mitochondrial dysfunction and synaptic damage in STZ/i.c.v rats. Importantly, we found that the hyperphosphorylation of tau in the hippocampus of STZ/i.c.v rats was decreased after oral administration of ertugliflozin, which was accompanied by decreased Phospho.IRS-1 Ser307 /Total.IRS-1 ratio and increased Phospho.Akt Ser473 /Total.Akt and Phospho.GSK3β Ser9 /Total.GSK3β ratios. Our results indicated that treatment with ertugliflozin reversed AD pathology, which may be associated with inhibition of insulin signaling disruption-induced tau hyperphosphorylation.
研究领域:
神经科学
·
药理学
·
神经退行性疾病
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认知障碍
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产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
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2020
·
IF 4.679
Rili Hao,Xinyu Song,Feng Li,Xintong Tan,Dongxiao Sun-Waterhouse,Dapeng Li
Exposure to nonbiodegradable cadmium (Cd) causes many health problems including the damage to the nervous system. This study aimed to increase knowledge about its neurotoxic effects and the neuroprotective potential of caffeic acid phenethyl ester (CAPE, a polyphenol abundant in honeybee propolis). In mice, CAPE (10 μmol/kg/day body weight) attenuated significantly learning and memory deficits induced by CdCl 2 (1.5 mg/kg/day body weight). For the CdCl 2 -treated mice, CAPE increased crossing number in open field test, decreased the alternation in Y-maze test, and increased the latency time and error number in step down test. CAPE also inhibited CdCl 2 -initiated Aβ accumulation and activation of pro-inflammatory factors and microglia in the brains. Therefore, CAPE could be a food-derived neuroprotective agent against Cd-induced neurotoxicity and neurodegenerative disorders, through attenuating neuronal apoptosis and neuroinflammation via the AMPK/SIRT1 pathway and amyloid-tau-neuroinflammation axis.
研究领域:
神经科学
·
毒理学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2025
·
IF 9.7
Meilin Zhu,Zhen Mao,Xinyu Li,Fenglin Chen,Yong Wang,Jiajia Guo,Xue Qiu
Quantum dots (QDs), with their tunable emission, high quantum yield, and superior photostability, have been widely employed as FRET donors or acceptors in ensemble measurements for transducting biomolecular interactions into measurable fluorescence signals. However, their implementation in single-molecule Förster resonance energy transfer (smFRET) remains limited, particularly for resolving intramolecular conformational dynamics. This gap stems from two inherent constraints: (1) their substantial hydrodynamic radii (5–15 nm) causing steric interference with biomolecular structures, and (2) stochastic bioconjugation approaches produce uncontrolled probe orientations that introduce uncertainty in FRET-derived distance calculations. Fluorescence cross-correlation spectroscopy (FCCS) overcomes these limitations by enabling solution-phase smFRET measurements, which provides an optimal framework for exploiting QDs in smFRET. Here, we challenged the QD-based smFRET system into measuring the conformational changes of intrinsically disordered tau proteins. Tau proteins were expressed with an N-terminal His-tag, enabling their direct and controllable immobilization on zinc-coated QDs via metal-coordination chemistry. The C-terminal Cys432 of mutant tau proteins were labeled with Cy5-maleimide as the acceptor to form a dual-labeled FRET system. Leveraging the large Förster distance (R 0 = 8.0 nm) of the QD605-Cy5 pair, pulsed interleaved excitation fluorescence cross-correlation spectroscopy (PIE-FCCS) quantified the distance from the QD center to C432—a structural metric reporting on global compaction. Strikingly, phosphorylated tau (P-tau) reduced this distance from 10.0 ± 1.0 nm to 6.9 ± 1.3 nm, indicating obvious monomeric compaction. Our study establishes QDs as potent tools for smFRET studies of biomolecular conformations and provides a straightforward approach for investigating the single-molecule conformations of intrinsically disordered proteins in physical environment.
研究领域:
生物物理学
·
分子生物学
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纳米技术
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神经科学
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单分子光谱学
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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）