scholarly journals MKP-1 reduces Aβ generation and alleviates cognitive impairments in Alzheimer’s disease models

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Yehong Du ◽  
Yexiang Du ◽  
Yun Zhang ◽  
Zhilin Huang ◽  
Min Fu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signaling Pathway ◽  
Amyloid Β ◽  
Gene Promoter ◽  
Long Term Potentiation ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase

AbstractMitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) is an essential negative regulator of MAPKs by dephosphorylating MAPKs at both tyrosine and threonine residues. Dysregulation of the MAPK signaling pathway has been associated with Alzheimer’s disease (AD). However, the role of MKP-1 in AD pathogenesis remains elusive. Here, we report that MKP-1 levels were decreased in the brain tissues of patients with AD and an AD mouse model. The reduction in MKP-1 gene expression appeared to be a result of transcriptional inhibition via transcription factor specificity protein 1 (Sp1) cis-acting binding elements in the MKP-1 gene promoter. Amyloid-β (Aβ)-induced Sp1 activation decreased MKP-1 expression. However, upregulation of MKP-1 inhibited the expression of both Aβ precursor protein (APP) and β-site APP-cleaving enzyme 1 by inactivating the extracellular signal-regulated kinase 1/2 (ERK)/MAPK signaling pathway. Furthermore, upregulation of MKP-1 reduced Aβ production and plaque formation and improved hippocampal long-term potentiation (LTP) and cognitive deficits in APP/PS1 transgenic mice. Our results demonstrate that MKP-1 impairment facilitates the pathogenesis of AD, whereas upregulation of MKP-1 plays a neuroprotective role to reduce Alzheimer-related phenotypes. Thus, this study suggests that MKP-1 is a novel molecule for AD treatment.

scholarly journals SkQ1 Suppresses the p38 MAPK Signaling Pathway Involved in Alzheimer’s Disease-Like Pathology in OXYS Rats

Antioxidants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 676
Author(s):  
Natalia A. Muraleva ◽  
Natalia A. Stefanova ◽  
Nataliya G. Kolosova
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signaling Pathway ◽  
P38 Mapk ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Oxys Rats ◽  
Mitogen Activated Protein Kinase ◽  
Immunofluorescent Staining ◽  
Αb Crystallin

Alzheimer’s disease (AD) is the most common type of dementia and is currently incurable, and mitogen-activated protein kinase (MAPK) p38 is implicated in the pathogenesis of AD. p38 MAPK inhibition is considered a promising strategy against AD, but there are no safe inhibitors capable of penetrating the blood–brain barrier. Earlier, we have shown that mitochondria-targeted antioxidant plastoquinonyl-decyltriphenylphosphonium (SkQ1) at nanomolar concentrations can prevent, slow down, or partially alleviate AD-like pathology in accelerated-senescence OXYS rats. Here we confirmed that dietary supplementation with SkQ1 during active progression of AD-like pathology in OXYS rats (aged 12–18 months) suppresses AD-like pathology progression, and for the first time, we showed that its effects are associated with suppression of p38 MAPK signaling pathway (MAPKsp) activity. Transcriptome analysis, western blotting, and immunofluorescent staining revealed that SkQ1 suppresses p38 MAPKsp activity in the hippocampus at the level of expression of genes involved in the p38 MAPKsp and reduces the phosphorylation of intermediate kinases (p38 MAPK and MK2) and a downstream protein (αB-crystallin). Thus, the anti-AD effects of SkQ1 are associated with improvement in the functioning of relevant signaling pathways and intracellular processes, thus making it a promising therapeutic agent for human AD.

scholarly journals Downregulation of TREM2 Expression Exacerbates Neuroinflammatory Responses Through TLR4-Mediated MAPK Signaling Pathway in a Transgenic Mouse Model of Alzheimer’s Disease

2021 ◽  
Author(s):  
John Bosco Ruganzu ◽  
Xiaoqian Peng ◽  
Yingying He ◽  
Xiangyuan Wu ◽  
Quzhao Zheng ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Mechanistic Study ◽  
Model Of Alzheimer’S Disease ◽  
Bv2 Cells ◽  
The Brain

Abstract Activation of glial cells and neuroinflammation play an important role in the onset and development of Alzheimer’s disease (AD). Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific receptor in the brain that is involved in regulating neuroinflammation. However, the precise effects of TREM2 on neuroinflammatory responses and its underlying molecular mechanisms in AD have not been studied in detail. Here, we employed a lentiviral-mediated strategy to downregulation of TREM2 expression on microglia in the brain of APPswe/PS1dE9 (APP/PS1) transgenic mice and BV2 cells. Our results showed that TREM2 downregulation significantly aggravated AD-related neuropathology including Aβ accumulation, peri-plaque microgliosis and astrocytosis, as well as neuronal and synapse-associated proteins loss, which was accompanied by a decline in cognitive ability. The further mechanistic study revealed that downregulation of TREM2 expression initiated neuroinflammatory responses through toll-like receptor 4 (TLR4)-mediated mitogen-activated protein kinase (MAPK) signaling pathway and subsequent stimulating the production of pro-inflammatory cytokines in vivo and in vitro. Moreover, blockade of p38, JNK, and ERK1/2 inhibited the release of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) induced by Aβ1−42 in TREM2-knocked down BV2 cells. Taken together, these findings indicated that TREM2 might be a potential therapeutic target for AD and other neuroinflammation related diseases.

scholarly journals TRIM22 Activates MAPK Signaling by Regulating the Transcription of SPHK2 and Accelerating the Degradation of Raf-1 in Glioblastoma

2021 ◽  
Author(s):  
Xiaowei Fei ◽  
Ya-nan Dou ◽  
Kai Sun ◽  
Jialiang Wei ◽  
Qingdong Guo ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Signaling Pathway ◽  
Mrna Level ◽  
Critical Role ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Luciferase Reporter ◽  
Exon 2

Abstract Background Tripartite motif (TRIM) 22 and mitogen-activated protein kinase (MAPK) signaling pathways play a critical role in tumor growth and therapeutic resistance of glioblastoma (GBM) respectively. However, the molecular mechanism between TRIM22 and MAPK signaling remains to be clarified. Methods We constructed TRIM22 knockout cell lines for molecular biology experiments, detected potential DNA fragments binding to TRIM22 by ChIP-Seq technology, and verified the sequencing results by ChIP-qPCR and CUT&Tag technology. In addition, we constructed different TRIM22 mutants to detect the binding of proteins in MAPK signaling pathway. Finally, the therapeutic effect was verified in NOD/SCID mice. The difference between the two groups of data conforming to the normal distribution was tested by Student t-test. Results Here, we found for the first time that TRIM22 acts as a transcription factor in the nucleus and binds to exon 2 of the transcript (NM_001204160) of SPHK2 gene to regulate its expression by ChIP-Seq technology, thus indirectly affecting the downstream MAPK signaling pathway. Knockout of TRIM22 using Cas9-sgRNAs resulted in decreased mRNA level of SPHK2 in GBM cells, while overexpression of TRIM22 enhanced it. The ERK1/2 driven luciferase reporter construct identified TRIM22 as a potential activator of MAPK signaling. Knockout and overexpression of TRIM22 regulate the inhibition and activation of MAPK signaling through its RING-finger domain. Co-immunoprecipitation demonstrated that TRIM22 bound to the negative regulator Raf-1 of MAPK signaling and accelerated its degradation by inducing K48-linked ubiquitination. The combination of the two is related to the CC domain and SPRY domain of TRIM22 and the C1D domain of Raf-1. TRIM22 also forms a complex with the downstream regulator ERK1/2 of MAPK and promotes K63-linked ubiquitination, resulting in the phosphorylation of ERK1/2. In addition, in vitro and in situ xenotransplantation models, SPHK2 inhibitor (K145), ERK1/2 inhibitor (Selumetinib) and non-phosphorylated mutant Raf-1S338A inhibited the growth promoting properties of TRIM22 in GBM cell line. Conclusions In conclusion, our study shows that TRIM22 regulates SPHK2 transcription as a transcription factor, indirectly affects MAPK signaling, and activates MAPK signaling through post-translational modification of two critical regulators of MAPK signaling in GBM cells.

scholarly journals Bu Shen Zhu Yun Decoction Improves Endometrial Receptivity via VEGFR-2-Mediated Angiogenesis

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Li Li ◽  
Huabo Jiang ◽  
Xuecong Wei ◽  
Dandan Geng ◽  
Ming He ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Embryo Implantation ◽  
Mapk Signaling ◽  
Endometrial Receptivity ◽  
Mapk Signaling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Cell Counting ◽  
Nuclear Antigen ◽  
Vitro Fertilization

Vascular endothelial growth factor receptor-2 (VEGFR-2) regulates the mitogen-activated protein kinase (MAPK) signaling pathway and plays an important role in angiogenesis. Bu Shen Zhu Yun decoction (BSZYD) can improve endometrial receptivity and embryo implantation rates in patients undergoing in vitro fertilization. However, whether BSZYD improves endometrial receptivity via angiogenesis remains unclear. Here, we investigated the effects of BSZYD on the proliferation, migration, and angiogenesis of human endometrial microvascular endothelial cells (HEMECs) and found that BSZYD upregulated the expression of cyclin D1, matrix metalloproteinase 9 (MMP9), and proliferating cell nuclear antigen (PCNA) in HEMECs. Cell Counting Kit 8 assay, scratch-wound assay, and Tube Formation Assay results showed that BSZYD promoted the proliferation, migration, and angiogenesis of HEMECs. Western blot analysis results revealed the activation of the MAPK signaling pathway by BSZYD through the upregulation of VEGF and VEGFR-2 expression. Together, these findings highlight the novel mechanism underlying BSZYD-mediated improvement in endometrial receptivity through the MAPK signaling pathway.

Neuroprotective properties of mitochondria-targeted antioxidants of the SkQ-type

2016 ◽  
Vol 27 (8) ◽  
pp. 849-855 ◽  
Author(s):  
Nickolay K. Isaev ◽  
Elena V. Stelmashook ◽  
Elisaveta E. Genrikhs ◽  
Galina A. Korshunova ◽  
Natalya V. Sumbatyan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Area ◽  
Hippocampal Slices ◽  
Amyloid Β ◽  
Long Term Potentiation ◽  
Term Potentiation ◽  
Neuroprotective Action

AbstractIn 2008, using a model of compression brain ischemia, we presented the first evidence that mitochondria-targeted antioxidants of the SkQ family, i.e. SkQR1 [10-(6′-plastoquinonyl)decylrhodamine], have a neuroprotective action. It was shown that intraperitoneal injections of SkQR1 (0.5–1 μmol/kg) 1 day before ischemia significantly decreased the damaged brain area. Later, we studied in more detail the anti-ischemic action of this antioxidant in a model of experimental focal ischemia provoked by unilateral intravascular occlusion of the middle cerebral artery. The neuroprotective action of SkQ family compounds (SkQR1, SkQ1, SkQTR1, SkQT1) was manifested through the decrease in trauma-induced neurological deficit in animals and prevention of amyloid-β-induced impairment of long-term potentiation in rat hippocampal slices. At present, most neurophysiologists suppose that long-term potentiation underlies cellular mechanisms of memory and learning. They consider inhibition of this process by amyloid-β1-42as anin vitromodel of memory disturbance in Alzheimer’s disease. Further development of the above studies revealed that mitochondria-targeted antioxidants could retard accumulation of hyperphosphorylated τ-protein, as well as amyloid-β1-42, and its precursor APP in the brain, which are involved in developing neurodegenerative processes in Alzheimer’s disease.

scholarly journals The oxygenated products of cryptotanshinone by biotransformation with Cunninghamella elegans exerting anti-neuroinflammatory effects by inhibiting TLR 4-mediated MAPK signaling pathway

2020 ◽  
Author(s):  
Jing-Shuai Wu ◽  
Qin-Yu Meng ◽  
Xiao-Hui Shi ◽  
Zhen-Kun Zhang ◽  
Hua-Shi Guan ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Transcriptome Analysis ◽  
Salvia Miltiorrhiza ◽  
Underlying Mechanism ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Cunninghamella Elegans ◽  
Chinese Medicinal Herb ◽  
Oxygenated Products

Abstract Background: Neuroinflammatory processes are critical in the development and progression of Alzheimer's disease (AD). The potent anti-neuroinflammatory inhibitors are expected as the candidates to treat AD. Cryptotanshinone (1), a major bioactive constituent in the traditional Chinese medicinal herb Dan-Shen Salvia miltiorrhiza Bunge, has been reported to possess remarkable pharmacological activities, especially anti-oxidation and anti-inflammation. Methods: Cryptotanshinone (1) was biotransformed with the fungus Cunninghamella elegans AS3.2028 to improve its bioactivities and physicochemical properties. The structures of transformed products were elucidated by comprehensive spectroscopic analysis including HRESIMS, NMR and ECD data. Their anti-neuroinflammatory activities were assessed by ELISA, transcriptome analysis, western blot, and immunofluorescence methods. Results: Three oxygenated products (2–4) at C-3 of cryptotanshinone (1) were obtained, among them 2 was a new compound. All of the biotransformed products (2–4) were found to inhibit significantly lipopolysaccharide-induced nitric oxide production in BV2 microglia cells with the IC50 values of 0.16‒1.16 μM, approximately 2‒20 folds stronger than the substrate (1). These biotransformed products also displayed remarkably improved inhibitory effects on the production of inflammatory cytokines (IL-1β, IL-6, TNF-α, COX-2 and iNOS) in BV-2 cells via targeting TLR4 compared to substrate (1). The underlying mechanism of 2 was elucidated by comparative transcriptome analysis, which suggested that it reduced neuroinflammatory mainly through mitogen-activated protein kinase (MAPK) signaling pathway. Western blotting results revealed that 2 downregulated LPS-induced phosphorylation of JNK, ERK, and p38 in MAPK signaling pathway. Conclusion: The biotransformed products of cryptotanshinone exhibit potent anti-neuroinflammatory activities. These findings provide a basal material for the discovery of candidates in treating AD.

scholarly journals P38α MAPK Signaling—A Robust Therapeutic Target for Rab5-Mediated Neurodegenerative Disease

2020 ◽  
Vol 21 (15) ◽  
pp. 5485
Author(s):  
Ursula A. Germann ◽  
John J. Alam
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Therapeutic Target ◽  
Kinase Inhibitors ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Therapeutic Effects ◽  
P38α Kinase

Multifactorial pathologies, involving one or more aggregated protein(s) and neuroinflammation are common in major neurodegenerative diseases, such as Alzheimer’s disease and dementia with Lewy bodies. This complexity of multiple pathogenic drivers is one potential explanation for the lack of success or, at best, the partial therapeutic effects, respectively, with approaches that have targeted one specific driver, e.g., amyloid-beta, in Alzheimer’s disease. Since the endosome-associated protein Rab5 appears to be a convergence point for many, if not all the most prominent pathogenic drivers, it has emerged as a major therapeutic target for neurodegenerative disease. Further, since the alpha isoform of p38 mitogen-activated protein kinase (p38α) is a major regulator of Rab5 activity and its effectors, a biology that is distinct from the classical nuclear targets of p38 signaling, brain-penetrant selective p38α kinase inhibitors provide the opportunity for significant therapeutic advances in neurogenerative disease through normalizing dysregulated Rab5 activity. In this review, we provide a brief summary of the role of Rab5 in the cell and its association with neurodegenerative disease pathogenesis. We then discuss the connection between Rab5 and p38α and summarize the evidence that through modulating Rab5 activity there are therapeutic opportunities in neurodegenerative diseases for p38α kinase inhibitors.

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