CHINESE JOURNAL OF CHEMICAL ENGINEERING
·
2022
·
IF 3.898
Huan-Huan Yin,Yin-Lei Han,Xiao Yan,Yi-Xin Guan
Occurrence of neurofibrillary tangles of the tau protein is a hallmark of tau-related neurodegenerative diseases, i.e. Alzheimer's disease (AD) and frontotemporal dementia. The pathological mechanism underlying AD remains poorly understood, and effective treatments are still unavailable to mitigate the disease. Inhibiting of tau aggregation and disrupting the existing fibrils are key targets in drug discovery towards preventing or curing AD. In this study, grape seed proanthocyanidins (GSPs) was found to effectively inhibit the repeat domain of tau (tau-RD) aggregation and disaggregate tau-RD fibrils in a concentration-dependent manner by inhibiting β-sheet formation of tau-RD. In cells, GSPs relieved cytotoxicity induced by tau-RD aggregates. Molecular dynamics simulations indicated that strong hydrogen bonding, hydrophobic interaction and π-π stacking between GSPs and tau-RD protein were major reasons why GSPs had high inhibitory activity on tau-RD fibrillogenesis. These results provide preliminary data to develop GSPs into medicines, foodstuffs or nutritional supplements for AD patients, suggesting that GSPs could be a candidate molecule in the drug design for AD therapeutics.
研究领域:
神经科学
·
药理学
·
分子生物学
·
药物发现
✓ 已验证
产品关联
DOI
高影响因子
ACS Nano
·
2021
·
IF 15.881
Heng Sun,Yan Zhong,Xiandi Zhu,Hongwei Liao,Jiyoung Lee,Ying Chen,Lijuan Ma,Jiafeng Ren,Meng Zhao,Mengjiao Tu,Fangyuan Li,Hong Zhang,Mei Tian,Daishun Ling
The hyperphosphorylated and aggregated tau accumulation represents a significant pathological hallmark of tauopathies including Alzheimer’s disease (AD), which is highly associated with defective autophagy in neuronal cells. Autophagy-activating strategies demonstrate the therapeutic potential for AD in many studies; however, further development is limited by their low efficacy and serious side effects that result from a lack of selectivity for diseased cells. Herein, we report a tauopathy-homing nanoassembly (THN) with autophagy-activating capacity for AD treatment. Specifically, the THN can bind to hyperphosphorylated and/or aggregated tau and selectively accumulate in cells undergoing tauopathy. The THN further promotes the clearance of pathogenic tau accumulation by stimulating autophagic flux, consequently rescuing neuron viability and cognitive functions in AD rats. This study presents a promising nanotechnology-based strategy for tauopathy-homing and autophagy-mediated specific removal of pathogenic tau in AD.
研究领域:
神经科学
·
纳米技术
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2019
·Vol. 20
·期 3
·487
·
IF 4.183
Xuexia Li,Xiubo Du,Jiazuan Ni
Alzheimer’s disease (AD) is a neurodegenerative disease with high morbidity that has received extensive attention. However, its pathogenesis has not yet been completely elucidated. It is mainly related to β-amyloid protein deposition, the hyperphosphorylation of tau protein, and the loss of neurons. The main function of tau is to assemble tubulin into stable microtubules. Under pathological conditions, tau is hyperphosphorylated, which is the major component of neurofibrillary tangles (NFT) in AD. There is considerable evidence showing that the dyshomeostasis of Zn2+is closely related to the development of AD. Herein, by using the third repeat unit of the microtubule-binding domain of tau (tau-R3), we investigated the effect of Zn2+on the aggregation and neurotoxicity of tau. Experimental results showed that tau-R3 probably bound Zn2+via its Cys residue with moderate affinity (association constant (Ka) = 6.82 ± 0.29 × 104M−1). Zn2+accelerated tau-R3 aggregation and promoted tau-R3 to form short fibrils and oligomers. Compared with tau-R3, Zn2+-tau-R3 aggregates were more toxic to Neuro-2A (N2A) cells and induced N2A cells to produce higher levels of reactive oxygen species (ROS). The dendrites and axons of Zn2+-tau-R3-treated neurons became fewer and shorter, resulting in a large number of neuronal deaths. In addition, both tau-R3 and Zn2+-tau-R3 aggregates were found to be taken up by N2A cells, and more Zn2+-tau-R3 entered the cells compared with tau-R3. Our data demonstrated that Zn2+can aggravate tau-R3 aggregation and neurotoxicity, providing clues to understand the relationship between Zn2+dyshomeostasis and the etiology of Alzheimer’s disease.Keywords:tau-R3;Zn2+;aggregation;neurotoxicity
研究领域:
神经科学
·
分子生物学
·
病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ALZHEIMERS DISEASE
·
2015
·Vol. 49
·期 3
·829-844
·
IF 4.151
Shan Ye,Wang Dan-Dan,Xu Yu-Xia,Wang Chu,Cao Lan,Liu Yun-Sheng,Zhu Cui-Qing
Stress is an important risk factor of Alzheimer’s disease (AD). It has been evidenced that stress could induce tau phosphorylation and increase tau insolubility in brain; however, little is known about the interactional effect of stress with aging on tauopathy. Therefore, we explored the effects of aging on stress-induced tauopathy and the potential mechanism in mouse model of chronic restraint stress (CRS). Here we found that in general, the level of phosphorylated tau (P-tau) was higher in brain of middle-aged mice than that in adult mice under physiological conditions. CRS-induced tau phosphorylation and its insolubility were more prominent in middle-aged mice. The increase of AT8-labeled insoluble P-tau was dramatic in middle-aged mice, which was highly ubiquitinated but did not form PHF structures. The levels of chaperones were relatively lower in middle-aged mice brain; CRS further reduced the expression, especially for HDJ2/HSP40. CRS also suppressed the expression of Pin1, the peptidylprolyl cis/trans isomerase, in middle-aged mice but not in adult mice. Downregulation of HSP40 or Pin1 caused an increase of transfected extraneous tau in 293 cells. Rosmarinic acid (RA) could effectively suppress the elevation of P-tau and insoluble P-tau formation induced by CRS, and reversed the abnormal changes of chaperones and Pin1 particularly in middle-aged mice. Taken together, our findings provided evidence that aging could be a promoting factor in stress-induced tauopathy, which was relevant with malregulation of chaperones and Pin1, and RA might be a promising beneficial agent for stress-induced tauopathy.
研究领域:
神经科学
·
药理学
·
老年学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Translational Neurodegeneration
·
2022
·Vol. 11
·期 1
·1-19
·
IF 9.883
Chen Dongmei,Lan Guihua,Li Ruomeng,Mei Yingxue,Shui Xindong,Gu Xi,Wang Long,Zhang Tao,Gan Chen-Ling,Xia Yongfang,Hu Li,Tian Yuan,Zhang Mi,Lee Tae Ho
Background Intracellular accumulation of the microtubule-associated protein tau and its hyperphosphorylated forms is a key neuropathological feature of Alzheimer’s disease (AD). Melatonin has been shown to prevent tau hyperphosphorylation in cellular and animal models. However, the molecular mechanisms by which melatonin attenuates tau hyperphosphorylation and tau-related pathologies are not fully understood.Methods Immunofluorescence, immunoblotting analysis and thioflavin-S staining were employed to examine the effects of early and late treatment of melatonin on tau-related pathology in hTau mice, in which nonmutated human tau is overexpressed on a mouse tau knockout background. High-throughput microRNA (miRNA) sequencing, quantitative RT-PCR, luciferase reporter assay and immunoblotting analysis were performed to determine the molecular mechanism.Results We found that both early and late treatment of melatonin efficiently decreased the phosphorylation of soluble and insoluble tau at sites related to AD. Moreover, melatonin significantly reduced the number of neurofibrillary tangles (NFTs) and attenuated neuronal loss in the cortex and hippocampus. Furthermore, using miRNA microarray analysis, we found that miR-504-3p expression was upregulated by melatonin in the hTau mice. The administration of miR-504-3p mimics dramatically decreased tau phosphorylation by targeting p39, an activator of the well-known tau kinase cyclin-dependent kinase 5 (CDK5). Compared with miR-504-3p mimics alone, co-treatment with miR-504-3p mimics and p39 failed to reduce tau hyperphosphorylation.Conclusion sOur results suggest for the first time that melatonin alleviates tau-related pathologies through upregulation of miR-504-3p expression by targeting the p39/CDK5 axis and provide novel insights into AD treatment strategies.
研究领域:
神经科学
·
分子生物学
·
神经退行性疾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2018
·
IF 13.709
Qing Chen,Yang Du,Kai Zhang,Zeyu Liang,Jinquan Li,Hao Yu,Rong Ren,Jin Feng,Zhiming Jin,Fangyuan Li,Jihong Sun,Min Zhou,Qinggang He,Xiaolian Sun,Hong Zhang,Mei Tian,Daishun Ling
Alzheimer’s disease (AD) remains an incurable disease and lacks efficient diagnostic methods. Most AD treatments have focused on amyloid-β (Aβ) targeted therapy; however, it is time to consider the alternative theranostics due to accumulated findings of weak correlation between Aβ deposition and cognition, as well as the failures of Phase III clinical trial on Aβ targeted therapy. Recent studies have shown that the tau pathway is closely associated with clinical development of AD symptoms, which might be a potential therapeutic target. We herein construct a methylene blue (MB, a tau aggregation inhibitor) loaded nanocomposite (CeNC/IONC/MSN-T807), which not only possesses high binding affinity to hyperphosphorylated tau but also inhibits multiple key pathways of tau-associated AD pathogenesis. We demonstrate that these nanocomposites can relieve the AD symptoms by mitigating mitochondrial oxidative stress, suppressing tau hyperphosphorylation, and preventing neuronal death both in vitro and in vivo. The memory deficits of AD rats are significantly rescued upon treatment with MB loaded CeNC/IONC/MSN-T807. Our results indicate that hyperphosphorylated tau-targeted multifunctional nanocomposites could be a promising therapeutic candidate for Alzheimer’s disease.
研究领域:
神经科学
·
药学
·
纳米技术
·
治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Chemical Biology
·
2025
·
IF 3.8
Jinying Gu,Chenxi He,Zeyu Han,Qifei Huang,Yanyi He,Yun Lu,Qidong You,Qiuyue Zhang,Lei Wang
Hyperphosphorylation of proteins is implicated in various diseases, such as phosphorylated Tau (p-Tau), which is the main cause of Alzheimer’s disease (AD). Dephosphorylation strategies have still been limited. Currently, phosphatase recruitment chimeras (PHORCs) have become a potential strategy for accelerating the dephosphorylation of proteins. However, PHORCs are still in the proof-of-concept stage. The paucity of available phosphatase effectors and the lack of effective methods to identify the appropriate length of the linker impede the development of PHORCs. Protein phosphatase 5 (PP5) is responsible for dephosphorylation of p-Tau in the brain. PP5 is distinct from other phosphatases, with a unique activation mechanism. We demonstrated that PP5 can be simultaneously recruited and activated for the design of PHORCs, exhibiting a synergistic advantage for accelerating dephosphorylation of p-Tau. Moreover, we attempted computation-aided prediction methods to obtain the potential length of the linker, promoting the rational design of PHORCs. Therefore, our study provides critical insights into the development of PHORCs and proposes new ideas for accelerating the design of heterotrimeric chimeras.
研究领域:
生物化学
·
神经科学
·
药物开发
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOLOGICAL CHEMISTRY
·
2025
·
IF 3.9
Junjie Wu,Keke Chai,Ying Tu,Kang Fang,Shuo Shi,Xiaochun Hu,Jihong Liu,Tianming Yao
Tau aggregation inhibitors or neurotoxic-metal chelators have been extensively studied as potential treatment for Alzheimer’s disease. However, it is a great challenge to improve their therapeutic effects while reducing neurotoxicity. Herein, we designed and synthesized two new compounds, (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetrakis((3,4,5-trihydroxyphenyl)methanone) ( 4GA ) and (4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis((3,4,5-trihydroxyphenyl)methanone) ( 2GA ). Each molecule is composed of a 1,4,7,10-tetraazacyclododecane (cyclen) core as the supramolecular chelator to copper ions, attached by 2 or 4 gallic acid polyphenol arms to capture tau peptide chain like a molecular hairpin. We interestingly found 4GA and 2GA could inhibit self-aggregation through blocking the misfolding of tau peptide, suppress the promotion of Cu 2+ on tau aggregation by removing Cu 2+ from dyshomeostasis, and clear reactive oxygen species (ROS) triggered by Cu 2+ using their reductive gallic acid groups. More significantly, the synthesized compounds exhibit remarkable efficiency on both in vitro and at cellular level. Our rational design of multifunctional therapeutic agent that simultaneously targets tau misfolding process, copper dyshomeostasis and oxidative stress of ROS, may hold considerable implications for the treatment of AD.
研究领域:
神经科学
·
药物化学
·
生物无机化学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Chemical Neuroscience
·
2023
·
IF 5
Yu-Qing Liu,Chu-Qiao Liang,Zhi-Wei Chen,Jun Hu,Jin-Jian Hu,Yun-Yi Luo,Yong-Xiang Chen,Yan-Mei Li
Tau plays a major role in Alzheimer’s disease (AD) and several other neurodegenerative diseases. Tau undergoing liquid–liquid phase separation (LLPS) performs specific physiological functions, induces pathological processes, and contributes to neurodegeneration. Regulating Tau phase separation helps maintain physiological functions of Tau and inhibits pathological aggregation. Here, we show that the 14-3-3 zeta isoform (14-3-3ζ) participates in Tau LLPS. 14-3-3ζ can undergo co-phase separation with WT Tau, participate in and stabilize Tau droplets, and inhibit Tau droplet-driven tubulin assembly. On the other hand, 14-3-3ζ disrupts the LLPS of phosphorylated and glycated Tau, thereby inhibiting the amyloid aggregation initiated by LLPS.
研究领域:
神经科学
·
分子生物学
·
细胞生物学
·
神经退行性疾病
✓ 已验证
DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
·
2022
·
IF 8.008
Chengjie Duan,Wenting Cheng,Yanheng Yao,Dayong Li,Zhongyun Wang,Yang Xiang
Aptamer-based methods have attracted increasing interest due to flexible engineering, but their generality is limited by the heterogeneity of signal transduction mechanisms. Given the fact that nonlinear and large molecules are more likely to make the nanosurface overloaded, we investigated a novel signal transduction process to extend the application of aptasensors. In this work, an aptamer complementary element (ACE) is designed with a primer region to serve as the signal probe, which can fully hybridize with an aptamer and be separated by magnetic beads (MBs). Upon target binding, the formed aptamer/target complex is much larger than the linear aptamer/ACE-primer dimer, causing overload of MBs on account of steric hindrance. An extra aptamer/ACE-primer can escape from the surface to the supernatant, which can be amplified by a catalytic hairpin assembly (CHA) circle. The size-dependent signal transduction and the modular design endow the method with high generality and flexibility for protein analysis. The proposed aptasensor was successfully applied to the detection of tau proteins ranging from 0.5 to 1000 ng mL–1 with a limit of detection (LOD) as low as 0.254 ng mL–1. The recovery tests in both human serum and cerebra spinal fluid confirmed the high accuracy and stability. Furthermore, a successful distinction was made between AD patients and healthy controls by the method, suggesting the possible applicability for practical analysis of tau proteins.
研究领域:
生物化学
·
分子诊断
·
分析化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BRAIN
·
2021
·Vol. 144
·期 9
·2759-2770
·
IF 13.501
Zhang Yalun,Zhang Yi,Aman Yahyah,Ng Cheung Toa,Chau Wing-Hin,Zhang Zhigang,Yue Ming,Bohm Christopher,Jia Yizhen,Li Siwen,Yuan Qiuju,Griffin Jennifer,Chiu Kin,Wong Dana S M,Wang Binbin,Jin Dongyan,Rogaeva Ekaterina,Fraser Paul E,Fang Evandro F,St George-Hyslop Peter,Song You-Qiang
The molecular link between amyloid-β plaques and neurofibrillary tangles, the two pathological hallmarks of Alzheimer’s disease, is still unclear. Increasing evidence suggests that amyloid-β peptide activates multiple regulators of cell cycle pathways, including transcription factors CDKs and E2F1, leading to hyperphosphorylation of tau protein. However, the exact pathways downstream of amyloid-β-induced cell cycle imbalance are unknown. Here, we show that PAX6, a transcription factor essential for eye and brain development which is quiescent in adults, is increased in the brains of patients with Alzheimer’s disease and in APP transgenic mice, and plays a key role between amyloid-β and tau hyperphosphorylation. Downregulation of PAX6 protects against amyloid-β peptide-induced neuronal death, suggesting that PAX6 is a key executor of the amyloid-β toxicity pathway. Mechanistically, amyloid-β upregulates E2F1, followed by the induction of PAX6 and c-Myb, while Pax6 is a direct target for both E2F1 and its downstream target c-Myb. Furthermore, PAX6 directly regulates transcription of GSK-3β, a kinase involved in tau hyperphosphorylation and neurofibrillary tangles formation, and its phosphorylation of tau at Ser356, Ser396 and Ser404. In conclusion, we show that signalling pathways that include CDK/pRB/E2F1 modulate neuronal death signals by activating downstream transcription factors c-Myb and PAX6, leading to GSK-3β activation and tau pathology, providing novel potential targets for pharmaceutical intervention.
研究领域:
神经科学
·
分子生物学
·
病理学
✓ 已验证
DOI
PubMed
高影响因子
Insects
·
2023
·Vol. 14
·期 7
·591
·
IF 3
Pingfan Jia,Xiaoyu Zhang,Bo Wang,Qinge Ji
Simple SummaryThe Solanaceae crops are the main hosts ofZeugodacus tau, a pest insect that causes serious damage to economically important crops of Solanaceae. In the winter–spring period, female adults ofZ. tauhave been found to oviposit on the pepino melonSolanum muricatum. However, the differences in the ability of the fruits ofS. muricatumand other Solanaceae crops to attract gravidZ. taufemales have not been clarified. In this study, oviposition and trapping bioassays were performed to clarify whether such differences existed. GC-MS was used to identify the compounds and relative contents of the volatile odors ofS. muricatum. The Y-tube olfactometer system was used to determine the compounds that induced behavioral responses in gravidZ. taufemales. The results show thatSolanum muricatumodor was attractive forZ. taufemales. The nine compounds from the volatiles ofS. muricatuminduce behavioral responses in gravidZ. taufemales. These results are beneficial for preventingZ. taufemales from harmingS. muricatum, developing attractants and repellents forZ. taufemales, and establishing a system of ecological control forZ. taufemales.AbstractZeugodacus tau(Walker) (Diptera: Tephritidae) is a pest seriously harmful to Solanaceae crops and was found to oviposit on the pepino melonSolanum muricatum(Aiton). To date, the differences in the ability of the fruits ofS. muricatumand other Solanaceae crops to attract gravidZ. taufemales have seldom been reported. Oviposition and trapping bioassays were performed to clarify whether such differences existed. A combination of GC-MS and the Y-tube olfactometer system was used to identify and determine the compounds inducing behavioral responses in gravidZ. taufemales to the volatile odors ofS. muricatum. The results show thatS. muricatumodors play a role in attracting gravidZ. taufemales. The odors of Solanaceae crops influence their ability to attract these organisms. The nine compounds from the volatiles ofS. muricatuminduce tendency or repellency responses in gravidZ. taufemales. Hexyl acetate, butyl acetate, amyl actate, and isoamyl acetate caused tendency behavior in gravidZ. taufemales, while hexyl hexanoate, butyl isovalerate, butyl valerate, and isoamyl hexanoate caused repellency behavior. Heptyl acetate caused repellency behavior in gravidZ. taufemales at higher concentrations (5 mg/mL) but caused tendency behavior at a low concentration (0.5 mg/mL). These results suggest that vigilance against the harm caused byZ. tauis required during the cultivation ofS. muricatum. The nine compounds of the volatile odors ofS. muricatumcould help to develop attractants and repellents for gravidZ. taufemales. These results are beneficial for preventingZ. taufemales from harmingS. muricatum, developing attractants and repellents forZ. taufemales, and establishing a system of ecological control forZ. taufemales.Keywords:Zeugodacus tau;Solanum muricatum;induced oviposition;attraction rate;volatile
研究领域:
昆虫学
·
植物保护
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）