INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Xiaodan Xiao,Yanfei Guan,Huiyu Mo,Kaizhao Lv,Jiaxin Chen,Jiaxing Xie,Qiguang Meng,Jianqi Liu,Yongkeng Lu,Feng Gao,Qingzhuang Chen
Alzheimer's disease (AD) is a neurodegenerative disorder with unclear etiology. This study employs single-cell RNA sequencing (scRNA-seq), high-throughput transcriptome sequencing, 16s rRNA sequencing, and animal experiments to investigate the role of the contactin-associated protein like-4 (Cntnap4) gene in AD and its interaction with intestinal flora. We found that Cntnap4 deficiency in AD mice led to increased Tau protein phosphorylation, amyloid-beta plaque accumulation, and neuronal loss. Astrocytes in Cntnap4 −/− mice showed impaired amyloid-beta processing. 16 s rRNA sequencing revealed distinct intestinal flora compositions between Cntnap4 −/− and control mice, indicating a potential link between gut microbiota and AD progression. Notably, GABA supplementation improved cognitive impairment, restored synaptic currents, reduced amyloid-beta plaques, and increased neuronal counts. This study highlights Cntnap4's critical role in AD and suggests gut-brain axis involvement, offering novel insights for potential therapeutic strategies.
研究领域:
神经退行性疾病
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分子生物学
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神经科学
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微生物组研究
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转化医学
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DOI
PubMed
高影响因子
BIOMATERIALS
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2023
·
IF 14
Jingyuan Wang,Zekun Wang,Yuqing Li,Yajun Hou,Chenyang Yin,Endong Yang,Ziyu Liao,Cundong Fan,Lisandra L. Martin,Dongdong Sun
Alzheimer's disease (AD) as a common neurodegenerative disease showed progressive cognitive dysfunction and behavioral impairment. Currently, the deposition of amyloid β-protein (Aβ) remains the main pathomechanism. However, preventing neuronal death induced by Aβ remains elusive, and no effective strategy in clinic was found to combat AD. Herein, a multifunctional double selenium nanosphere (CLNDSe) was designed and prepared, and A 2A AR agonist (CGS) modification endowed CLNDSe NPs with A 2A AR-targeted blood brain barrier (BBB) delivery in vitro and in vivo . CLNDSe NPs after modification of LPFFD short peptide effectively inhibited Aβ 42 aggregation and attenuated Aβ 42 -induced neural toxicity by inhibiting oxidative damage and mitochondrial dysfunctions. Nerve growth factor (NGF) linked to large Se sphere significantly attenuated Tau phosphorylation and gliocytes activation in APP/PS1 mice. CLNDSe NPs administration in vivo also effectively restored GPX1/4 antioxidant ability, alleviated neural loss and neurofibrillary tangles, prevented neural ferroptosis, and eventually ameliorated cognitive deficits of APP/PS1 mice. Importantly, CLNDSe NPs showed good safety and biocompatibility. Taken together, our finding validated the rational design that BBB-targeted delivery of double selenium nanosphere may be a novel strategy to ameliorate Alzheimer's disease by inhibiting neural ferroptosis.
研究领域:
神经科学
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纳米技术
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药理学
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神经退行性疾病
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DOI
高影响因子
Biology-Basel
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2025
·Vol. 14
·期 9
·1114
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IF 3.5
Jin Li,Jiawen Wang,Yaodong Li,Jingyi Guo,Ziliang Jin,Shourong Qiao,Yunxia Zhang,Guoyin Li,Huazhen Liu,Changjing Wu
Simple SummaryAlzheimer’s disease is a severe, gradually worsening brain disorder leading to memory loss and dementia, with no effective treatments currently available. In this study, we investigated a natural compound called mulberroside A, derived from the mulberry plant, to determine its potential protective effects against Alzheimer’s disease. Utilizing a mouse model and human brain cells, we discovered that mulberroside A enhanced memory and decreased brain cell damage. Additionally, it increased the levels of crucial brain chemicals, facilitating better communication between nerve cells. Moreover, it alleviated harmful stress in the brain and reduced the formation of two hallmark pathologies: toxic tau protein tangles and amyloid plaques. The compound significantly decreased phosphorylated tau—a key driver of neuronal degeneration—while simultaneously inhibiting amyloid plaque formation. Mulberroside A operated by activating specific neuroprotective pathways that promote brain health, including those that encourage nerve growth. These findings indicate it could serve as a promising new treatment to slow or prevent Alzheimer’s disease by targeting multiple disease mechanisms.Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, with current therapies offering only limited symptomatic relief and lacking disease-modifying efficacy. Addressing this critical therapeutic gap, natural multi-target compounds like mulberroside A (MsA)—a bioactive glycoside fromMorus albaL.—present promising alternatives. This study investigated MsA’s neuroprotective potential using scopolamine-induced AD-like mice and N2a/APP695swe cells. In vivo, MsA significantly ameliorated cognitive deficits and neuronal loss, concurrently enhancing cholinergic neurotransmission through increased acetylcholine levels and inhibited acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) activities. MsA also upregulated neurotrophic factors (BDNF, CREB) in critical brain regions. In vitro, MsA restored cholinergic function, mitigated oxidative stress, and crucially reduced amyloid-β (Aβ) production by dual regulation of APP processing: promoting the non-amyloidogenic pathway via ADAM10 upregulation and inhibiting the amyloidogenic pathway via suppression of BACE1 and γ-secretase components. Mechanistically, these multi-target benefits were mediated by MsA’s activation of the PI3K/AKT pathway, which triggered downstream inhibitory phosphorylation of GSK3β—directly reduced tau hyperphosphorylation—and activation of CREB/BDNF signaling. Collectively, our findings demonstrate that MsA confers comprehensive neuroprotection against AD pathology by simultaneously targeting cholinergic dysfunction, oxidative stress, Aβ accumulation, tau phosphorylation, and impaired neurotrophic signaling, highlighting its strong therapeutic candidacy.
研究领域:
神经科学
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药理学
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生物化学
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分子生物学
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药物化学
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神经退行性疾病
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2023
·
IF 8.2
Licong Yang,Yabin Wang,Guodong Zheng,Zhiwei Li,Jingtao Mei
Resveratrol (Res) is a common natural polyphenol that inhibits inflammation and oxidative stress in Alzheimer's disease (AD). However, the absorption efficiency and in vivo bioactivity of Res are poor. High fat diet-induced metabolic disorders, including obesity and insulin resistance, can promote AD-related β-amyloid (Aβ) aggregation, Tau protein phosphorylation and neurotoxicity. Gut microbiota play a role in modulating metabolic syndrome and cognitive impairment. Herein, flower-like Res-loaded selenium nanoparticles/chitosan nanoparticles ( [email protected] @Res-CS-NPs) with higher loading capacity (64 %) were prepared to regulate gut microbiota in cases of AD with metabolic disorder. The nano-flowers could restore gut microbiota homeostasis to reduce lipopolysaccharide (LPS) formation and LPS-induced neuroinflammation. Additionally, [email protected] @Res-CS-NPs can prevent lipid deposition and insulin resistance by decreasing Firmicutes levels and increasing Bacteroidetes levels in the gut, further inhibiting Aβ aggregation and Tau protein phosphorylation through the JNK/AKT/GSK3β signaling pathway. Moreover, [email protected] @Res-CS-NPs treatment was able to regulate the relative levels of gut microbiota associated with oxidative stress, inflammation and lipid deposition, including Entercoccus , Colidextribacter , Rikenella , Ruminococcus , Candidatus_Saccharimonas , Alloprevotella and Lachnospiraceae_UCG-006 . Overall, [email protected] @Res-CS-NPs significantly enhances cognitive ability in AD mice with metabolic disorder, highlighting their potential for preventing cognitive impairments in AD.
研究领域:
神经科学
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药理学
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生物技术
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微生物学
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代谢学
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产品关联
DOI
PubMed
高影响因子
FARADAY DISCUSSIONS
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2016
·Vol. 196
·335-350
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IF 3.544
Jun Wang,Yinglong Wu,Fang Zeng,Shuailing Huang,Shuizhu Wu
Fluorophores with aggregation-induced emission (AIE) characteristics are attractive and versatile tools for both chemical sensing and biological imaging. Herein, we designed and synthesized a fluorescent light-up system CTPE-Tau with enhanced cellular uptake ability. The system possesses several advantages, such as a large Stokes shift, low cytotoxicity, and good photostability. Also, it has been successfully utilized to track esterase-activated release of taurine and to scavenge intracellular ROS, and shows great potential for trackable visualized therapy.
研究领域:
化学传感
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生物成像
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诊疗学
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产品关联
DOI
PubMed
高影响因子
DRUG DELIVERY
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2018
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IF 3.095
Shengnuo Fan,Yuqiu Zheng,Xuan Liu,Wenli Fang,Xiaoyu Chen,Wang Liao,Xiuna Jing,Ming Lei,Enxiang Tao,Qiulan Ma,Xingmei Zhang,Rui Guo,Jun Liu
Alzheimer’s disease is a neurodegenerative disorder mainly characterized by β-amyloid deposit and tau hyperphosphorylation with no curative treatments. Curcumin (Cur) has been proved to have potential use in Alzheimer’s disease with its anti-amyloid, anti-inflammatory, and anti-oxidant properties, etc. However, its hydrophobicity and low bioavailability hinder its application. In this paper, we designed a novel brain-target nanoparticle, poly(lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-PEG) conjugated with B6 peptide and was loaded with Cur (PLGA-PEG-B6/Cur) and administered it into HT22 cells and APP/PS1 Al transgenic mice. The in vitro assays including dynamic light scattering (DLS), flow cytometry (FCM), red blood cell (RBC) lysis, and thromboelastography (TEG) analysis indicated that this nanoparticle could narrow the diameter of Cur, increase its cellular uptake and possess good blood compatibility. The results from Morris water maze proved that PLGA-PEG-B6/Cur could tremendously improve the spatial learning and memory capability of APP/PS1 mice, compared with native Cur. The ex vivo assays including Bielschowsky silver staining, immunostaining, and western blotting demonstrated that PLGA-PEG-B6/Cur could reduce hippocampal β-amyloid formation and deposit and tau hyperphosphorylation. Thus, we suggested that PLGA-PEG-B6/Cur nanoparticles would be of potential and promising use for the treatment of Alzheimer’s disease.
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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神经退行性疾病
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2021
·
IF 4.36
Feng-mao An,Zheng Liu,Xin-ran Xuan,Qing-shan Liu,Cheng-xi Wei
Ethnopharmacological relevance The traditional Chinese medicine Sanweidoukou decoction (DK-3) was a classical formula for the treatment of nervous system diseases , recorded in the Chinese medical classic Sibu Yidian . Aim of the study The present study is aim to investigate the neuroprotective effects of DK-3 on β-amyloid (Aβ) protein -induced AD-like pathologies and underlying molecular mechanisms both in vitro and in vivo studies. Materials and methods Hydrolysates of DK-3 were analyzed by LC-ESI-MS/MS. In vitro , MTT was utilized to examine effects of DK-3 on Aβ 25-35 -induced cytotoxicity in PC12 cells. In vivo , male Sprague-Dawley rats were administered with Aβ 25-35 to induce AD-like pathologies and behavioral evaluations were conducted via Morris water maze (MWM) test. Histopathological changes were observed by Hematoxylin-eosin (HE) straining. Immunohistochemistry (IHC) was used to detect the tau hyperphosphorylation at Thr181 site. The expression levels of tau hyperphosphorylation, inflammation-related cytokines such as COX-2, iNOS , TNF-α, IL-1β, IL-6, the phosphorylated state of various mitogen-activated protein kinase (MAPK) signaling molecules (p38 MAPK, ERK, and JNK) and activation of nuclear factor κB (NF-κB) in vitro and in vivo were assessed via Western blot . Results In vitro , DK-3 dose-dependently increased cell viability of PC12 cells induced by Aβ 25-35 . In vivo , DK-3 improved learning and memory abilities of Aβ 25-35 -induced AD-like rats. Moreover, DK-3 reversed hyperphosphorylation of tau and reduced the production of inflammation-related cytokines through significantly inhibited MAPK and NF-κB signaling pathways both in vitro and in vivo studies. Conclusion The present study suggested that the traditional Chinese medicine DK-3 may play a role in preventing and treating AD by reducing the hyperphosphorylation of tau protein and the expressions of inflammation-related cytokines via modulating the MAPK/NF-κB signaling pathways.
研究领域:
中医
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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
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
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2022
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IF 7.088
Lei Pang,Jin Li,Zheng Liu,Yin-Sheng Quan,He Huan Sui,Yi Jia,Fener Chen,Jung Joon Lee,Peng Liu,Zhe-Shan Quan,Qing-Kun Shen,Hong-Yan Guo
An extensive study was performed to discover a series of novel 20( R )-panaxadiol derivatives with various substituents at the 3-OH position as nontoxic, brain-permeable, multi-target leads for treating Alzheimer's disease . In vitro analysis revealed that a compound bearing benzyl-substituted carbamate , which we denoted compound 14a , exhibited the most potent neuroprotective activity, with an EC 50 of 13.17 μM. The neuroprotective effect of compound 14a was slightly more potent than that of donepezil and much more potent than that of 20( R )-panaxadiol. Compound 14a at 7.5–120 μM exhibited low toxicity in various cell lines. In addition, compound 14a exhibited a wide range of biological activities , including inhibiting apoptosis ; inducing tau hyperphosphorylation ; affecting beta-amyloid (Aβ), β-secretase, reactive oxygen species , tumor necrosis factor-α, cyclooxygenase-2, and interleukin-1β production; and promoting Aβ 25-35 disaggregation. The effective permeability of compound 14a across the blood-brain barrier was 26.13 × 10 −6 cm/s, indicating that it can provide adequate exposure in the central nervous system. Further, compound 14a improved learning, memory, and novel object recognition in mice, and in vivo toxicity experiments confirmed a good therapeutic safety range. Thus, compound 14a is a promising multifunctional lead for treating Alzheimer's disease and offers new avenues for natural product-derived anti-Alzheimer's disease drugs.
研究领域:
药理学
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神经科学
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药物发现
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产品关联
DOI
PubMed
高影响因子
CNS Neuroscience & Therapeutics
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2024
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IF 4.8
Lu Wang,Yingjuan Wei,Zhenzhou Sun,Wenya Tai,Hui Li,Yaling Yin,Lin‐Hua Jiang,Jian‐Zhi Wang
Background Oxidative stress is a well‐known pathological factor driving neuronal loss and age‐related neurodegenerative diseases. Melatonin, coenzyme Q10 and lecithin are three common nutrients with an antioxidative capacity. Here, we examined the effectiveness of them administrated individually and in combination in protecting against oxidative stress‐induced neuronal death in vitro, and neurodegenerative conditions such as Alzheimer's disease and associated deficits in vivo. Methods Mouse neuroblastoma Neuro‐2a (N2a) cells were exposed with H 2 O 2 for 6 h, and subsequently treated with melatonin, coenzyme Q10, and lecithin alone or in combination for further 24 h. Cell viability was assessed using the CCK ‐8 assay. Eight‐week‐old male mice were intraperitoneally injected with D‐(+)‐galactose for 10 weeks and administrated with melatonin, coenzyme Q10 , lecithin, or in combination for 5 weeks starting from the sixth week, followed by behavioral tests to assess the effectiveness in mitigating neurological deficits, and biochemical assays to explore the underlying mechanisms. Results Exposure to H 2 O 2 significantly reduced the viability of N2a cells and increased oxidative stress and tau phosphorylation, all of which were alleviated by treatment with melatonin, coenzyme Q10, lecithin alone, and, most noticeably, by combined treatment. Administration of mice with D‐(+)‐galactose‐induced oxidative stress and tau phosphorylation, brain aging, impairments in learning and memory, anxiety‐ and depression‐like behaviors, and such detrimental effects were mitigated by melatonin, coenzyme Q10, lecithin alone, and, most consistently, by combined treatment. Conclusions These results suggest that targeting oxidative stress via supplementation of antioxidant nutrients, particularly in combination, is a better strategy to alleviate oxidative stress‐mediated neuronal loss and brain dysfunction due to age‐related neurodegenerative conditions.
研究领域:
神经科学
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药理学
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细胞生物学
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衰老研究
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Linyan Duan,Zhizhong Hao,Rong Ji,Xingfan Li,Hao Wang,Yujing Su,Fangxia Guan,Shanshan Ma
Alzheimer's disease (AD) is a chronic neurodegenerative disease with high prevalence, long duration and poor prognosis. The blood-brain barrier (BBB) is a physiologic barrier in the central nervous system, which hinders the entry of most drugs into the brain from the blood, thus affecting the efficacy of drugs for AD. Natural products are recognized as one of the promising and unique therapeutic approaches to treat AD. To improve the efficiency and therapeutic effect of the drug across the BBB, a natural polyphenolic compound, procyanidin C-1 (C1) was encapsulated in glucose-functionalized bovine serum albumin (BSA) nanoparticles to construct Glu-BSA/C1 NPs in our study. Glu-BSA/C1 NPs exhibited good stability, slow release, biocompatibility and antioxidant properties. In addition, Glu-BSA/C1 NPs penetrated the BBB, accumulated in the brain by targeting Glut1, and maintained the BBB integrity both in vitro and in vivo . Moreover, Glu-BSA/C1 NPs alleviated memory impairment of 5 × FAD mice by reducing Aβ deposition and Tau phosphorylation and promoting neurogenesis. Mechanistically, Glu-BSA/C1 NPs significantly activated the PI3K/AKT pathway and inhibited the NLRP3/Caspase-1/IL-1β pathway thereby suppressing neuroinflammation. Taken together, Glu-BSA/C1 NPs could penetrate the BBB and mitigate neuroinflammation in AD, which provides a new therapeutic approach targeting AD.
研究领域:
神经科学
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药理学
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纳米技术
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2019
·
IF 6.054
Xiaodong Dou,Huixia Huang,Yibo Li,Lan Jiang,Yanxing Wang,Hongwei Jin,Ning Jiao,Lihe Zhang,Liangren Zhang,Zhenming Liu
Alzheimer’s disease (AD) is one of the most challenging diseases around the world with no effective clinical treatment. Previous studies have suggested c-Jun N-terminal kinase 3 (JNK3) as an attractive therapeutic target for AD. Herein, we report 3-substituted indolin-2-one derivatives as the first isoform-selective JNK3 inhibitors by multistage screening. In this study, comparative structure-based virtual screening was performed, and J30-8 was identified with a half-maximal inhibitory concentration of 40 nM, which exhibited over 2500-fold isoform selectivity and marked kinome-wide selectivity. Further study indicated that 1 μM J30-8 exhibited neuroprotective activity in vitro so as to alleviate the spatial memory impairment in vivo through reducing plaque burden and inhibiting the phosphorylation of JNKs, Aβ precursor protein, and Tau protein. All of these indicated J30-8 as proved isoform-selective JNK3 inhibitors that might serve as a useful tool for further JNK3 studies with AD as well as for the development of JNK3 inhibitors for the potential treatment of neurodegenerative diseases.
研究领域:
神经科学
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药理学
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药物发现
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DOI
PubMed
高影响因子
BIOMATERIALS
·
2018
·
IF 8.806
Jing Sun,Chunfang Wei,Yanan Liu,Wenjie Xie,Mengmeng Xu,Hui Zhou,Jie Liu
Alzheimer's disease (AD) is a neurodegenerative disease with a complex pathogenesis. Controlled release , target ability, and multi-channel synergistic treatment are key factors associated with the success of AD drugs. Herein, we report a novel mesoporous nano-selenium (MSe) release delivery system (MSe-Res/Fc-β-CD/Bor) based on the borneol (Bor) target, β-cyclodextrin nanovalves (Fc-β-CD) with loaded resveratrol (Res). Previous experiments have shown that MSe-Res/Fc-β-CD/Bor first releases Bor by interacting with blood or intracellular esterases , allowing the nanosystem to pass through the blood-brain barrier (BBB). Subsequently, the Fc-β-CD is opened by the redox (H 2 O 2 ) response to the release of Res at the lesion site. We demonstrated that MSe-Res/Fc-β-CD/Bor inhibited aggregation of β-amyloid proteins (Aβ), mitigated oxidative stress , and suppressed tau hyperphosphorylation , while protecting nerve cells and successfully improving memory impairment in APP/PS1 mice. Interestingly, compared with rivastigmine (Riv) positive drugs alone, the MSe/Fc-β-CD/Bor loaded with Riv had a better pharmacokinetic index. These results indicate that MSe-Res/Fc-β-CD/Bor could be a prospective drug for treating AD.
研究领域:
神经学
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药学
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纳米技术
✓ 已验证
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）