BRAIN
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2021
·Vol. 144
·期 9
·2759-2770
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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
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分子生物学
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病理学
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DOI
PubMed
高影响因子
Frontiers in Aging Neuroscience
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2022
·
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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产品关联
DOI
PubMed
高影响因子
Frontiers in Aging Neuroscience
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2022
·
IF 5.702
Xiang-Yu Zheng,Hai-Chen Zhang,Yu-Dan Lv,Feng-Yan Jin,Xiu-Juan Wu,Jie Zhu,Yang Ruan
Background Patients with Alzheimer's disease (AD) have a significantly higher risk of seizures than other individuals in an age-matched population, suggesting a close association between epilepsy and AD. We aimed to examine the effects of levetiracetam (LEV)-a drug for treating seizures-on learning and memory and the neuropathological features of AD. Methods We crossbred APP23 mice with microtubule-associated protein tau (MAPT) transgenic mice to generate APP23/MAPT mice. These mice were treated with different concentrations of LEV in the presence of kainic acid (KA) for 3 months. Results Low doses of LEV alleviated the effects of KA on memory defects in APP23/MAPT mice. Mechanistic investigations showed that low concentrations of LEV decreased tau phosphorylation by reducing the activities of cyclin-dependent kinase 5 and glycogen synthase kinase 3α/β, thus rescuing neurons from synaptic dystrophy and apoptosis. Low doses of LEV inhibited the effects of KA (i.e., inducing neuroinflammation and impairing the autophagy of amyloid β-peptide), thus improving cognitive decline. High concentrations of LEV decreased the production and deposition of amyloid β-peptide (Aβ) by reducing the expression of β-site APP-cleaving enzyme 1 and presenilin 1. However, high concentrations of LEV also induced neuronal apoptosis, decreased movement ability in mice, and did not alleviate cognitive decline in AD mice. Conclusion Our results support the hypothesis that aberrant network activity contributes to the synaptic and cognitive deficits in APP23/MAPT mice. A low concentration of LEV may help ameliorate abnormalities of AD; however, a high LEV concentration did not induce similar results.
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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产品关联
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
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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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
Acta Pharmaceutica Sinica B
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2019
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IF 5.808
Fangfang Li,Zongliang Liu,Heyuan Sun,Chunmei Li,Wenyan Wang,Liang Ye,Chunhong Yan,Jingwei Tian,Hongbo Wang
Gliomas are the most common primary intracranial neoplasms among all brain malignancies, and the microtubule affinity regulating kinases (MARKs) have become potential drug targets for glioma. Here, we report a novel dual small-molecule inhibitor of MARK3 and MARK4, designated as PCC0208017. In vitro, PCC0208017 strongly inhibited kinase activity against MARK3 and MARK4, and strongly reduced proliferation in three glioma cell lines. This compound attenuated glioma cell migration, glioma cell invasion, and angiogenesis. Molecular mechanism studies revealed that PCC0208017 decreased the phosphorylation of Tau, disrupted microtubule dynamics, and induced a G2/M phase cell cycle arrest. In an in vivo glioma model, PCC0208017 showed robust anti-tumor activity, blood–brain barrier permeability, and a good oral pharmacokinetic profile. Molecular docking studies showed that PCC0208017 exhibited high binding affinity to MARK3 and MARK4. Taken together, our study describes for the first time that PCC0208017, a novel MARK3/MARK4 inhibitor, might be a promising lead compound for treatment of glioma.
研究领域:
肿瘤学
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药理学
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分子生物学
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神经科学
✓ 已验证
DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY
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2020
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IF 3.292
Zuntao Wu,Lin Bai,Runqi Tu,Lijie Zhang,Yue Ba,Huizhen Zhang,Xing Li,Xuemin Cheng,Wenjie Li,Hui Huang
Lead (Pb) is recognized as a potent inducer of synaptic toxicity generally associated with reduced synaptic transmission and increased neuronal fiber excitability, becoming an environmental risk for neurodegenerative processes. Despite numerous toxicological studies on Pb have been directed to the developing brain, attention concerning long-term consequences of pubertal chronic Pb exposure on neuronal activity is still lacking. Thus, we exposed 4-week-old male mice to 0.2 % lead acetate solution for one month, then, conducted behavioral tests or extracted brain homogenate from mice prefrontal cortex (PFC) and hippocampus at the age of 4, 13 and 16-month-old respectively. Our results showed that treated mice exhibited an evident increase in latency to reach platform following pubertal Pb exposure and aging. The increase of 8-OHdG revealed evident neural DNA oxidative damage across time upon pubertal Pb exposure. In the hippocampus of lead exposed mice at three age nodes, the expression of brain-derived neurotrophic factor precursor (proBDNF) increased, while that of mature BDNF (mBDNF), cAMP-response element binding protein (CREB) and phosphorylated CREB (pCREB) decreased compared with the control group. Furthermore, the expression of BACE1 protein and tau phosphorylation level in PFC and hippocampus increased, APP mRNAs in PFC and prolonged induction of BACE1 in hippocampus. Our results show that chronic Pb exposure from pubertal stage onward can either initiate divergent synaptic-related gene expression patterns in adulthood or trigger time-course of neurodegenerative profile within the PFC or hippocampus, which can contribute consistent deficits of cognition across subsequent age-nodes.
研究领域:
神经毒理学
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神经科学
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分子生物学
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行为科学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2024
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IF 5.7
Kun Hu,Shaojun Wu,Jiaxin Xu,Yongzhen Zhang,Yanan Zhang,Xinyuan Wu,Jie Miao,Yongxu Yao,Susu Zhu,Guangtong Chen,Jie Ren
Alzheimer’s disease (AD), one of the neurodegenerative disorders, is highly correlated with the abnormal hyperphosphorylation of Tau and aggregation of β-amyloid (Aβ). Oxidative stress, neuroinflammation, and abnormal autophagy are key drivers of AD and how they contribute to neuropathology remains largely unknown. The flavonoid compound pongamol is reported to possess a variety of pharmacological activities, such as antioxidant, antibacterial, and anti-inflammatory. This study investigated the neuroprotective effect and its mechanisms of pongamol in lipopolysaccharide (LPS)-induced BV2 cells, d-galactose/sodium nitrite/aluminum chloride (d-gal/NaNO2/AlCl3)-induced AD mice, and Caenorhabditis elegans models. Our research revealed that pongamol reduced the release of inflammatory factors IL-1β, TNF-α, COX-2, and iNOS in LPS-induced BV2 cells. Pongamol also protected neurons and significantly restored memory function, inhibited Tau phosphorylation, downregulated Aβ aggregation, and increased oxidoreductase activity in the hippocampus of AD mice. In addition, pongamol reversed the nuclear transfer of NF-κB and increased the levels of Beclin 1 and LC3 II/LC3 I. Most importantly, the anti-inflammatory and promoter autophagy effects of pongamol may be related to the regulation of the Akt/mTOR signaling pathway. In summary, these results showed that pongamol has a potential neuroprotective effect, which greatly enriched the research on the pharmacological activity of pongamol for improving 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
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
CARBOHYDRATE POLYMERS
·
2023
·
IF 11.2
Licong Yang,Yabin Wang,Zhiwei Li,Xiaohua Wu,Jingtao Mei,Guodong Zheng
The pathology of Alzheimer's disease (AD) is highly correlated with obesity-induced insulin resistance. Resveratrol (Res) is a natural phenol that demonstrates a neuroprotective effect, but the bioactivity of Res is low in vivo . Here, chitosan (CS) was cross-linked with sodium tripolyphosphate (TPP) to encapsulate low water solubility Res. Next, a brain-targeted peptide (TG: TGNYKALHPHNG) was modified on the surface of Res-loaded CS/TPP nanoparticles (TG-Res-CS/TPP-NPs) to specifically deliver Res to the brain. Morris water maze results indicated that cognitive impairments were ameliorated by TG-Res-CS/TPP-NPs in obesity-related AD mice. Obesity-related insulin resistance promotes Tau phosphorylation and Aβ aggregation in the brain. Administration of TG-Res-CS/TPP-NPs alleviated lipid deposition-induced insulin resistance and decreased the level of phosphorylated Tau and Aβ aggregation via the JNK/AKT/GSK3β pathway. Additionally, TG-Res-CS/TPP-NPs transported across blood-brain barrier which in turn increased glucose transporter expression levels, antioxidant enzyme activity and inhibited microglial cell activation . Thus, TG-Res-CS/TPP-NPs were more effective than Res-CS/TPP-NPs at regulating glucose homeostasis , oxidative stress and neuroinflammation in the brain. Moreover, inflammatory , lipid metabolism and oxidative stress-related gut microbiota including Helicobacter , Colidextribacter , Anaerotruncus , Parasutterella , Allobaculum , Alloprevotella , Alistipes , Bifidobacterium and Candidatus_Saccharimonas were also regulated by TG-Res-CS/TPP-NPs. This work indicates the potential use of TG-Res-CS/TPP-NPs for the delivery of Res.
研究领域:
药理学
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神经科学
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分子生物学
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生物技术
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微生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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