The low levels of nerve growth factor and its upstream regulatory kinases in prion infection is reversed by resveratrol

Hu, Chao; Cao, Chen; Chen, Jia; Xiao, Kang; Wang, Jing; Shi, Qi; Ma, Yue; Gao, Liping; Wu, Yue-Zhang; Xia, Ying; Yan, Pu; Maimaitiming, Adalaiti; Zhou, Donghua H.; Zhang, Lina; Chen, Zhibao; Dong, Xiao‐Ping

doi:10.1016/j.neures.2019.12.019

Cited by 10 publications

(7 citation statements)

References 33 publications

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“…It not only emphasizes the original role of prions in activating cellular Gal-3-TREM2 signaling but also implies a reversible process of the prion-triggered activation of Gal-3. In fact, clearance of prions in the susceptible cell lines reverses, at least partially, the aberrant expressions of some neuronal agents, such as NGF and relevant cascade 45 and M-CSF and its receptor CSF1R. 46 Apparently, such a reversible effect via the removal of prions on dysregulated biological pathways in the cultured cells cannot simply extrapolate to the pathology of the naturally occurring prion disease or the experimental prion infection.…”

Section: ■ Discussionmentioning

confidence: 99%

Increased Gal-3 Mediates Microglia Activation and Neuroinflammation via the TREM2 Signaling Pathway in Prion Infection

Fan,

Wu,

Jia

et al. 2023

ACS Chem. Neurosci.

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Galectin 3 (Gal-3) is one of the major elements for activating microglia and mediating neuroinflammation in some types of neurodegenerative diseases. However, its role in the pathogenesis of prion disease is seldom addressed. In this study, markedly increased brain Gal-3 was identified in three scrapie-infected rodent models at the terminal stage. The increased Gal-3 was mainly colocalized with the activated microglia. Coincidental with the increased brain Gal-3 in prion-infected animals, the expression of brain trigger receptor expressed in myeloid cell 2 (TREM2), one of the Gal-3 receptors, and some components in the downstream pathway also significantly increased, whereas Toll-like receptor 4 (TLR4), another Gal-3 receptor, and the main components in its downstream signaling were less changed. The increased Gal-3 signals were distributed at the areas with PrPSc deposit but looked not to colocalize directly with PrPSc/PrP signals. Similar changing profiles of Gal-3, the receptors TREM2 and TLR4, as well as the proteins in the downstream pathways were also observed in prion-infected cell line SMB-S15. Removal of PrPSc replication in SMB-S15 cells reversed the upregulation of cellular Gal-3, TREM2, and the relevant proteins. Moreover, we presented data for interactions of Gal-3 with TREM2 and with TLR4 morphologically and molecularly in the cultured cells. Stimulation of prion-infected cells or their normal partner cells with recombinant mouse Gal-3 in vitro induced obvious responses for activation of TREM2 signaling and TLR4 signaling. Our data here strongly indicate that prion infection or PrPSc deposit induces remarkably upregulated brain Gal-3, which is actively involved in the microglia activation and neuroinflammation mainly via TREM2 signaling.

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Section: ■ Discussionmentioning

confidence: 99%

Increased Gal-3 Mediates Microglia Activation and Neuroinflammation via the TREM2 Signaling Pathway in Prion Infection

Fan,

Wu,

Jia

et al. 2023

ACS Chem. Neurosci.

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“…Subsequently, brain sections were subjected to permeate with 0.3% Triton X-100 in PBS for 30 min and blocked with normal goat serum for 1 h. After blocked, sections were incubated with anti-mGluR5 (1:200, AB5675, Merck, United States), anti-mGluR1 (1:200, 12551S, CST, United States), anti-NeuN (Neuronal specific nuclear protein, 1:200, MAB377, Merck, United States), anti-GFAP (glial fibrillary acidic protein, 1:200, #3670, CST, United States), and anti-iba1 (Ion calcium-binding bridle molecule 1, 1:200, SAB2702364, Sigma, United States) in dilution solution (PBS with 2% BSA and 0.3% Triton X-100) at 4 °C overnight. The sections were subsequently incubated with 1:200-diluted Alexa Fluor 488-labeled goat-derived anti-rabbit (1:200, A11034, Invitrogen, United States) and Alexa Fluor 568-labeled goat-derived anti-mouse (1:200, A11031, Invitrogen, United States) secondary antibodies at 37 °C for 1 h. After removing secondary antibodies, DAPI were used to stain the nucleus at final concentration of 1 mg/ml at RT for 30 min ( Hu et al, 2021 ). Slices were sealed and the images of the targeting proteins were viewed and analyzed using high-content screening system (Operetta Enspire, Perkin Elmer, United States) or confocal microscopy (LEICA TCS SP8, Germany).…”

Section: Methodsmentioning

confidence: 99%

Different Aberrant Changes of mGluR5 and Its Downstream Signaling Pathways in the Scrapie-Infected Cell Line and the Brains of Scrapie-Infected Experimental Rodents

Chen

Xia

et al. 2022

Front. Cell Dev. Biol.

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Metabotropic glutamate receptor subtype 5 (mGluR5) is a G-protein-coupled receptor found widely in the central nervous system. It has been involved in the development and progression of some neurodegenerative diseases, but its role in prion diseases is rarely described. In this study, the changes of mGluR5 and its downstream signaling pathways in prion-infected cell line SMB-S15 and the brains of scrapie-infected experimental rodents were evaluated by various methodologies. We found the levels of mGluR5 were significantly increased in a prion-infected cell line SMB-S15 and the cultured cells transiently express an abnormal form PrP (Cyto-PrP). Using immunoprecipitation tests and immunofluorescent assays (IFA), molecular interaction and morphological colocalization between PrP and mGluR5 were observed in the cultured cells. We identified that the (GPCRs)-IP3-IP3R-Ca2+ pathway was activated and the levels of the downstream kinases p38, ERK, and JNK were increased in SMB-S15 cells. After treated with mGluR5 antagonist (MTEP) or the removal of prion replication by resveratrol in SMB-S15 cells, the upregulations of mGluR5 and the downstream kinases were restored in a certain degree. Moreover, increased mGluR5 contributes to the cell damage in prion-infected cells. Contrarily, the levels of mGluR5 in the brains of several scrapie-infected rodent models were decreased at terminal stage. IFA of the brain sections of scrapie-infected rodents demonstrated that the signals of mGluR5 were preferentially colocalized with the NeuN-positive cells, accompanying with severe neuron losses in Nissl staining, which might be a reason for the decrease of mGluR5. Our data indicate the different aberrant alterations of mGluR5 and the downstream signaling pathways during prion infection in vivo and in vitro.

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“…Besides inhibiting prion replications, this polyphenolic compound can ameliorate the expression of NGF through CaMKK2/CaMKIV (calcium/calmodulin-dependent protein kinase 2/calcium/calmodulin-dependent protein kinase type 4) cascade. 232 Resveratrol can have great potential in treating and alleviating symptoms of other neurodegenerative diseases such as AD, PD, and ALS. 233−235 Resveratrol can significantly enhance the antioxidant response and simultaneously increase the estrogen levels in AD.…”

Section: ■ Neurodegenerative Diseasesmentioning

confidence: 99%

“…Moreover, it can be used to remove the replications of prion proteins in prion diseases through recovering the levels of cerebral nerve growth factor (NGF) after the removal of PrPSc (utilizing 10 μM of resveratrol within 7 days makes the SMB-S15 cells, which are scrapie-infected cell lines to be treated). Besides inhibiting prion replications, this polyphenolic compound can ameliorate the expression of NGF through CaMKK2/CaMKIV (calcium/calmodulin-dependent protein kinase 2/calcium/calmodulin-dependent protein kinase type 4) cascade …”

Section: Neurodegenerative Diseasesmentioning

confidence: 99%

Role of Polyphenols on Gut Microbiota and the Ubiquitin-Proteasome System in Neurodegenerative Diseases

Nargeh

Aliabadi

Ajami

2021

J. Agric. Food Chem.

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Today, neurodegenerative diseases have become a remarkable public health challenge due to their direct relation with aging. Accordingly, understanding the molecular and cellular mechanisms occurring in the pathogenesis of them is essential. Both protein aggregations as a result of the ubiquitin–proteasome system (UPS) inefficiency and gut microbiota alternation are the main pathogenic hallmarks. Polyphenols upregulating this system may decrease the developing rate of neurodegenerative diseases. Most of the dietary intake of polyphenols is converted into other microbial metabolites, which have completely different biological properties from the original polyphenols and should be thoroughly investigated. Herein, several prevalent neurodegenerative diseases are pinpointed to explain the role of gut microbiota alternations and the role of molecular changes, especially UPS down-regulation in their pathogenesis. Some of the most important polyphenols found in our diet are explained along with their microbial metabolites in the body.

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The low levels of nerve growth factor and its upstream regulatory kinases in prion infection is reversed by resveratrol

Cited by 10 publications

References 33 publications

Increased Gal-3 Mediates Microglia Activation and Neuroinflammation via the TREM2 Signaling Pathway in Prion Infection

Increased Gal-3 Mediates Microglia Activation and Neuroinflammation via the TREM2 Signaling Pathway in Prion Infection

Different Aberrant Changes of mGluR5 and Its Downstream Signaling Pathways in the Scrapie-Infected Cell Line and the Brains of Scrapie-Infected Experimental Rodents

Role of Polyphenols on Gut Microbiota and the Ubiquitin-Proteasome System in Neurodegenerative Diseases

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