scholarly journals TRPML1 Participates in the Progression of Alzheimer’s Disease by Regulating the PPARγ/AMPK/Mtor Signalling Pathway

2017 ◽  
Vol 43 (6) ◽  
pp. 2446-2456 ◽  
Author(s):  
Lu Zhang ◽  
Yu Fang ◽  
Xuan Cheng ◽  
Yajun Lian ◽  
Hongliang Xu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Expression ◽  
Cell Viability ◽  
Neuronal Apoptosis ◽  
Signalling Pathway ◽  
Primary Neurons ◽  
Expression Levels ◽  
Related Proteins

Background: TRPML1 is reported to be involved in the pathogenesis of Alzheimer’s disease (AD) by regulating autophagy; however, the underlying mechanism is not completely clear. Methods: We developed an APP/PS1 transgenic animal model that presents with AD. TRPML1 was also overexpressed in these mice. Protein expression levels were determined by Western blot. Morris water maze (MWM) and recognition tasks were performed to characterize cognitive ability. TUNEL assays were analysed for the detection of neuronal apoptosis. Primary neurons were isolated and treated with the vehicle, Aβ1-42 or Aβ1-42 + mTOR activator, as well as infected with the recombinant adenovirus TRPML1 overexpression vector in vitro. Cell viability was measured by the MTS assay, and lysosomal Ca2+ was also measured. Results: In the APP/PS1 transgenic mice, TRPML1 was downregulated, the PPARγ/AMPK signalling pathway was activated, the mTOR/S6K signalling pathway was suppressed, and autophagic lysosome reformation (ALR)-related proteins were upregulated. TRPML1 overexpression or treatment with PPARγ and AMPK inhibitors or an mTOR activator reduced the expression levels of ALR-related proteins, rescued the memory and recognition impairments and attenuated neuronal apoptosis in mice with the APP/PS1 transgenes. In vitro experiments showed that TRPML1 overexpression or treatment with the mTOR activator propranolol attenuated the Aβ1-42-suppressed cell viability and the Aβ1-42-decreased lysosomal [Ca2+] ion concentration in primary neurons. TRPML1 overexpression or treatment with the mTOR activator propranolol also attenuated the Aβ1-42-inhibited mTOR/S6K signalling pathway and the Aβ1-42-induced ALR-related protein expression levels. Conclusion: TRPML1 is involved in the pathogenesis of AD by regulating autophagy at least in part through the PPARγ/AMPK/mTOR signallingpathway.

scholarly journals Extract of Cynomorium songaricum ameliorates mitochondrial ultrastructure impairments and dysfunction in two different in vitro models of Alzheimer’s disease

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Dan Cheng ◽  
Lei Su ◽  
Xu Wang ◽  
Xinjie Li ◽  
Lingling Li ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Intracellular Calcium ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Ultrastructure ◽  
Expression Levels ◽  
Intracellular Atp ◽  
Study Results ◽  
Related Proteins

Abstract Background Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders, but there is still no effective way to stop or slow its progression. Our previous studies demonstrated that extract of Cynomorium songaricum (ECS), a Chinese herbal medicine, had neuroprotective effects in AD models in vivo. However, the pharmacological mechanism of ECS in AD is still unclear. Methods To study the mechanisms of action of the effects of ECS on AD, we used Aβ25–35- and H2O2-exposed HT22 cells to mimic specific stages of AD in vitro. The mitochondrial membrane potential (MMP), intracellular ATP, intracellular reactive oxygen species (ROS), and expression levels of mitochondrial dynamics-related proteins in each group were examined. Furthermore, we explored the mechanisms by which ECS reduces the phosphorylation of Drp1 at Ser637 and the changes in the concentrations of intracellular calcium ions in the two models after FK506 intervention. Results The results showed that ECS significantly enhanced the MMP (P < 0.05), increased intracellular ATP levels (P < 0.05) and decreased intracellular ROS levels in the Aβ- and H2O2-induced cell models (P < 0.05). Additionally, ECS regulated the expression levels of mitochondrial dynamics-related proteins by reducing the phosphorylation of Drp1 at Ser637 (P < 0.05) and decreasing the expression of Fis1 in the H2O2-induced models (P < 0.05). Further study indicated that ECS reduced the overload of intracellular calcium (P < 0.05). Conclusion Our study results suggest that ECS protects the mitochondrial ultrastructure, ameliorates mitochondrial dysfunction, and maintains mitochondrial dynamics in AD models.

scholarly journals Network Pharmacology-Based Study of the Underlying Mechanisms of Huangqi Sijunzi Decoction for Alzheimer’s Disease

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Wei Zhang ◽  
Mingti Lv ◽  
Yating Shi ◽  
Yonghui Mu ◽  
Zhaoyang Yao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuroprotective Effect ◽  
Signalling Pathway ◽  
Signalling Pathways ◽  
Network Pharmacology ◽  
Neuroprotective Effects ◽  
Target Network ◽  
Compound Target

Background. Huangqi Sijunzi decoction (HQSJZD) is a commonly used conventional Chinese herbal medicine prescription for invigorating Qi, tonifying Yang, and removing dampness. Modern pharmacology and clinical applications of HQSJZD have shown that it has a certain curative effect on Alzheimer’s disease (AD). Methods. The active components and targets of HQSJZD were searched in the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The genes corresponding to the targets were retrieved using UniProt and GeneCard database. The herb-compound-target network and protein-protein interaction (PPI) network were constructed by Cytoscape. The core targets of HQSJZD were analysed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The main active compounds of HQSJZD were docked with acetylcholinesterase (AChE). In vitro experiments were conducted to detect the inhibitory and neuroprotective effects of AChE. Results. Compound-target network mainly contained 132 compounds and 255 corresponding targets. The main compounds contained quercetin, kaempferol, formononetin, isorhamnetin, hederagenin, and calycosin. Key targets contained AChE, PTGS2, PPARG, IL-1B, GSK3B, etc. There were 1708 GO items in GO enrichment analysis and 310 signalling pathways in KEGG, mainly including the cAMP signalling pathway, the vascular endothelial growth factor (VEGF) signalling pathway, serotonergic synapses, the calcium signalling pathway, type II diabetes mellitus, arginine and proline metabolism, and the longevity regulating pathway. Molecular docking showed that hederagenin and formononetin were the top 2 compounds of HQSJZD, which had a high affinity with AChE. And formononetin has a good neuroprotective effect, which can improve the oxidative damage of nerve cells. Conclusion. HQSJZD was found to have the potential to treat AD by targeting multiple AD-related targets. Formononetin and hederagenin in HQSJZD may regulate multiple signalling pathways through AChE, which might play a therapeutic role in AD.

scholarly journals STIM1 deficiency is linked to Alzheimer’s disease and triggers cell death in SH-SY5Y cells by upregulation of L-type voltage-operated Ca2+ entry

2018 ◽  
Vol 96 (10) ◽  
pp. 1061-1079 ◽  
Author(s):  
Carlos Pascual-Caro ◽  
Maria Berrocal ◽  
Aida M. Lopez-Guerrero ◽  
Alberto Alvarez-Barrientos ◽  
Eulalia Pozo-Guisado ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Protein Expression ◽  
Transmembrane Domain ◽  
Neuroblastoma Cell ◽  
Disease Patient ◽  
List Type

Abstract STIM1 is an endoplasmic reticulum protein with a role in Ca2+ mobilization and signaling. As a sensor of intraluminal Ca2+ levels, STIM1 modulates plasma membrane Ca2+ channels to regulate Ca2+ entry. In neuroblastoma SH-SY5Y cells and in familial Alzheimer’s disease patient skin fibroblasts, STIM1 is cleaved at the transmembrane domain by the presenilin-1-associated γ-secretase, leading to dysregulation of Ca2+ homeostasis. In this report, we investigated expression levels of STIM1 in brain tissues (medium frontal gyrus) of pathologically confirmed Alzheimer’s disease patients, and observed that STIM1 protein expression level decreased with the progression of neurodegeneration. To study the role of STIM1 in neurodegeneration, a strategy was designed to knock-out the expression of STIM1 gene in the SH-SY5Y neuroblastoma cell line by CRISPR/Cas9-mediated genome editing, as an in vitro model to examine the phenotype of STIM1-deficient neuronal cells. It was proved that, while STIM1 is not required for the differentiation of SH-SY5Y cells, it is absolutely essential for cell survival in differentiating cells. Differentiated STIM1-KO cells showed a significant decrease of mitochondrial respiratory chain complex I activity, mitochondrial inner membrane depolarization, reduced mitochondrial free Ca2+ concentration, and higher levels of senescence as compared with wild-type cells. In parallel, STIM1-KO cells showed a potentiated Ca2+ entry in response to depolarization, which was sensitive to nifedipine, pointing to L-type voltage-operated Ca2+ channels as mediators of the upregulated Ca2+ entry. The stable knocking-down of CACNA1C transcripts restored mitochondrial function, increased mitochondrial Ca2+ levels, and dropped senescence to basal levels, demonstrating the essential role of the upregulation of voltage-operated Ca2+ entry through Cav1.2 channels in STIM1-deficient SH-SY5Y cell death. Key messages STIM1 protein expression decreases with the progression of neurodegeneration in Alzheimer’s disease. STIM1 is essential for cell viability in differentiated SH-SY5Y cells. STIM1 deficiency triggers voltage-regulated Ca2+ entry-dependent cell death. Mitochondrial dysfunction and senescence are features of STIM1-deficient differentiated cells.

scholarly journals Isoforsythiaside Attenuates Alzheimer’s Disease via Regulating Mitochondrial Function Through the PI3K/AKT Pathway

2020 ◽  
Vol 21 (16) ◽  
pp. 5687 ◽  
Author(s):  
Chunyue Wang ◽  
Jie Hao ◽  
Xin Liu ◽  
Chenliang Li ◽  
Xuyang Yuan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Viability ◽  
Mitochondrial Function ◽  
B Cell Lymphoma ◽  
Akt Pathway ◽  
Mitochondrial Apoptosis ◽  
Expression Levels ◽  
The Brain ◽  
Apoptosis Proteins

Improving mitochondrial dysfunction and inhibiting apoptosis has always been regarded as a treatment strategy for Alzheimer’s disease (AD). Isoforsythiaside (IFY), a phenylethanoid glycoside isolated from the dried fruit of Forsythia suspensa, displays antioxidant activity. This study examined the neuroprotective effects of IFY and its underlying mechanisms. In the L-glutamate (L-Glu)-induced apoptosis of HT22 cells, IFY increased cell viability, inhibited mitochondrial apoptosis, and reduced the intracellular levels of reactive oxygen species (ROS), caspase-3, -8 and -9 after 3 h of pretreatment and 12–24 h of co-incubation. In the APPswe/PSEN1dE9 transgenic (APP/PS1) model, IFY reduced the anxiety of mice, improved their memory and cognitive ability, reduced the deposition of beta amyloid (Aβ) plaques in the brain, restrained the phosphorylation of the tau protein to form neurofibrillary tangles, inhibited the level of 4-hydroxynonenal in the brain, and improved phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway-related mitochondrial apoptosis. In Aβ1-42-induced U251 cells, IFY relieved the mitochondrial swelling, crest ruptures and increased their electron density after 3 h of pretreatment and 18–24 h of co-incubation. The improved cell viability and mitochondrial function after IFY incubation was blocked by the synthetic PI3K inhibitor LY294002. Taken together, these results suggest that IFY exerts a protective effect against AD by enhancing the expression levels of anti-apoptosis proteins and reducing the expression levels of pro-apoptosis proteins of B-cell lymphoma-2 (BCL-2) family members though activating the PI3K/AKT pathway.

scholarly journals Investigating Markers of the NLRP3 Inflammasome Pathway in Alzheimer’s Disease: A Human Post-Mortem Study

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1753
Author(s):  
Hao Tang ◽  
Michael Harte
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Expression ◽  
Glial Cell ◽  
Nlrp3 Inflammasome ◽  
Cell Activation ◽  
Temporal Cortex ◽  
Activation Markers

Neuroinflammatory mechanisms with glial cell activation have been implicated in the pathogenic process of Alzheimer’s disease (AD). Activation of the NLRP3 inflammasome is an essential component of the neuroinflammatory response. A role for NLRP3 activation in AD is supported by both in vitro and in vivo preclinical studies with little direct investigation of AD brain tissue. RNA expression of genes of three glial cell markers, HLA-DRA, AIF-1 and GFAP; the components of the NLRP3 inflammasome NLRP3, ASC, and caspase-1; and downstream pre-inflammatory cytokines IL-1 β and IL-18, were investigated in the temporal cortex of AD patients and age- and sex-matched controls. Protein expression of GFAP was also assessed. Increases in both mRNA and protein expression were observed for GFAP in AD. There were no significant changes in other NLRP3 activation markers between groups. Our results indicate the involvement of astrocyte activation in AD, particularly in more severe patients. We found no evidence for the specific involvement of the NLRP3 inflammasome.

scholarly journals Tert-Butylhydroquinone Prevents Oxidative Stress-Mediated Apoptosis and Extracellular Matrix Degradation in Rat Chondrocytes

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Bo Yang ◽  
Haisheng Huang ◽  
Qisong He ◽  
Wei Lu ◽  
Lu Zheng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Extracellular Matrix ◽  
Matrix Metalloproteinase ◽  
Protein Expression ◽  
Cell Viability ◽  
Cell Counting ◽  
Expression Levels ◽  
Extracellular Matrix Components ◽  
Mrna And Protein Expression

Oxidative stress-induced chondrocyte apoptosis and degradation of the extracellular matrix (ECM) play an important role in the progression of osteoarthritis (OA). In addition, tert-butylhydroquinone (TBHQ) is an activator of the nuclear factor erythroid derived-2-related factor 2 (Nrf2). The present study aimed to determine the effectiveness of TBHQ in preventing the apoptosis of chondrocytes and degradation of the extracellular matrix, induced by oxidative stress, in vitro. Therefore, rat chondrocytes were exposed to 20 μM tert-butyl hydroperoxide (TBHP) for 24 h to establish an oxidative damage model, in vitro. Thereafter, cell viability was evaluated using the Cell Counting Kit-8 assay. Moreover, the level of ROS was determined through 2′,7′-dichlorofluorescein diacetate staining. The mitochondrial membrane potential of chondrocytes was also measured using JC-1. Furthermore, cell apoptosis was assessed through Annexin V-fluorescein isothiocyanate/propidium iodide staining. The study also performed Western blotting and qPCR to evaluate the expression of extracellular matrix components, matrix catabolic enzymes, and changes in signalling pathways. The results showed that 2.5 and 5 μM of TBHQ reduced the TBHP-induced generation of excessive ROS and improved cell viability. Additionally, 2.5 and 5 μM of TBHQ prevented mitochondrial damage and apoptosis in rat chondrocytes. Treatment with TBHQ also increased the mRNA and protein expression levels of aggrecan and collagen II. However, TBHQ reduced the mRNA and protein expression levels of matrix metalloproteinase 3 (MMP3) and matrix metalloproteinase 13 (MMP13) in rat chondrocytes. In addition, treatment with TBHQ enhanced the protein expression levels of Nrf2, NADPH quinone oxidoreductase 1 (NQO-1), and hemeoxygenase-1 (HO-1) in rat chondrocytes. The current study showed that TBHQ was not only effective in protecting against TBHP-induced oxidative stress but also inhibited the apoptosis of rat chondrocytes and degradation of the ECM by activating the Nrf2 pathway. The results therefore suggest that TBHQ holds potential for use in the treatment of OA.

Up-regulation of LDL receptor-related protein expression in Alzheimer's disease and in vitro

2000 ◽  
Vol 21 ◽  
pp. 192
Author(s):  
Zhihua Qiu ◽  
Dudley K. Strickland ◽  
Bradley T. Hyman ◽  
G. William Rebeck
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Expression ◽  
Ldl Receptor ◽  
Related Protein

scholarly journals Tortoise Plastron and Deer Antler Gelatin Prevents Against Neuronal Mitochondrial Dysfunction In Vitro: Implication for a Potential Therapy of Alzheimer’s Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Dan Cheng ◽  
Xin-Jing Yang ◽  
Lu Zhang ◽  
Zong-Shi Qin ◽  
Wen-Qi Li ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Oxidative Damage ◽  
Cell Viability ◽  
Mitochondrial Dysfunction ◽  
Dependent Manner ◽  
Deer Antler ◽  
Mitochondrial Dynamic ◽  
Aberrant Expression

Mitochondrial dysfunction with oxidative damage plays the fundamental roles in the pathogenesis of Alzheimer’s disease. In traditional Chinese medicine (TCM) practice, animal tissue-derived gelatins are often used as nootropic agents to treat cognitive deterioration and senile dementia. Tortoise plastron gelatin (TPG) and deer antler gelatin (DAG) are the two most commonly used gelatins for this purpose. This study sought to examine the effects of the two gelatins in preventing neuronal mitochondria from oxidative damage. PC12 cells, a cell line derived from rat pheochromocytoma, exposed to the neurotoxin Aβ25–35 served as an in vitro model of Alzheimer’s disease. The cells were separately pre-treated with TPG and DAG at various concentrations ranging from 6.26 µg/ml–200 µg/ml, followed by co-incubation with 20 μM Aβ25–35 for different duration. Cell viability, mitochondrial membrane potential (MMP) and ultrastructure, intracellular ATP, reactive oxygen species (ROS) and calcium (Ca2+) level, the expression of mitochondrial dynamic proteins and biomarkers of apoptosis were measured. Pretreatment with TPG and DAG reversed the Aβ-induced reduction of cell viability in a dose-dependent manner. Both TPG and DAG significantly increased MMP and ATP, alleviated the accumulation of damaged mitochondrial fragments, and normalized the aberrant expression of multiple mitochondrial dynamic proteins of the Aβ-exposed cells. Both gelatins also suppressed intracellular ROS overproduction and Ca2+ overload, overexpression of cytochrome c and pro-apoptosis biomarkers induced by the Aβ exposure. These results suggest that TPG and DAG may have the anti-dementia potential by preventing neuronal mitochondria from oxidative damage.

scholarly journals Study on the Multitarget Synergistic Effects of Kai-Xin-San against Alzheimer’s Disease Based on Systems Biology

2019 ◽  
Vol 2019 ◽  
pp. 1-15
Author(s):  
Sirui Guo ◽  
Jiahong Wang ◽  
Yunjia Wang ◽  
Ying Zhang ◽  
Kaishun Bi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Systems Biology ◽  
Synergistic Effects ◽  
Medicine Research ◽  
Related Proteins ◽  
Functional Mechanisms ◽  
The Brain

Kai-Xin-San (KXS), a classical Chinese traditional prescription, was widely applied in the treatment of Alzheimer’s disease (AD), while its functional mechanisms still remain unclear. By using systems biology approaches at animal, cellular, and molecular levels, the improvement of KXS on cognitive impairment was achieved by inhibiting abnormal acetylcholinesterase. The function on the nerve skeleton was performed by regulating the Tau phosphorylation pathway. Its antioxidant, anti-inflammatory, and antiapoptotic effects by modulating the aberrant upregulation of ROS, proinflammatory factors, and apoptosis-related proteins in the brain were studied to reveal the synergistic therapeutic efficacy of KXS. Then, formula dismantling in vitro indicated that ginseng was the principal herb, whereas three other herbs served adjuvant roles to achieve the best effect. After that, the in vivo analysis of components into plasma and brain of AD rats showed that 8 of 23 components in blood and 4 of 10 components in brain were from ginseng, respectively, further verifying the principal status of ginseng and the synergistic effects of the formula. Thus, the anti-AD effects of KXS were achieved by multitargets and multichannels. The systems biology approaches presented here provide a novel way in traditional herbal medicine research.

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