Activation of peroxisome proliferator‐activated receptor delta suppresses <scp>BACE</scp>1 expression by up‐regulating <scp>SOCS</scp>1 in a <scp>JAK</scp>2/<scp>STAT</scp>1‐dependent manner

Lee, Won Jin; Ham, Sun Ah; Lee, Gyeong Hee; Choi, Mi‐Jung; Yoo, Hyunjin; Paek, Kyung Shin; Lim, Dae‐Seog; Hong, Kwonho; Hwang, Jae Joon; Seo, Han Geuk

doi:10.1111/jnc.14715

Cited by 10 publications

(9 citation statements)

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“…A peptides directly and indirectly activate TLR4, the pattern recognition receptor for LPS (29,30). STAT1 tis sue concentration is increased in diseased regions of AD brain (31) and can regulate expression of  secretase 1, one of the endoproteases that sequentially catalyzes the hydrolysis of amyloid precursor pro tein to generate A peptides (32). STAT5 activation regulates micro glial activation and is required for monocytemediated synaptic degradation (33).…”

Section: Discussionmentioning

confidence: 99%

Single-cell peripheral immunoprofiling of Alzheimer’s and Parkinson’s diseases

et al. 2020

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Peripheral blood mononuclear cells (PBMCs) may provide insight into the pathogenesis of Alzheimer’s disease (AD) or Parkinson’s disease (PD). We investigated PBMC samples from 132 well-characterized research participants using seven canonical immune stimulants, mass cytometric identification of 35 PBMC subsets, and single-cell quantification of 15 intracellular signaling markers, followed by machine learning model development to increase predictive power. From these, three main intracellular signaling pathways were identified specifically in PBMC subsets from people with AD versus controls: reduced activation of PLCγ2 across many cell types and stimulations and selectively variable activation of STAT1 and STAT5, depending on stimulant and cell type. Our findings functionally buttress the now multiply-validated observation that a rare coding variant in PLCG2 is associated with a decreased risk of AD. Together, these data suggest enhanced PLCγ2 activity as a potential new therapeutic target for AD with a readily accessible pharmacodynamic biomarker.

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Section: Discussionmentioning

confidence: 99%

Single-cell peripheral immunoprofiling of Alzheimer’s and Parkinson’s diseases

et al. 2020

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“…It has been demonstrated that PPARδ activation may exert a neuroprotective effect in AD models by inhibiting the inflammation and the amelioration of Aβ 1-42 -induced hippocampal neurotoxicity ( 58 , 59 ). Additionally, PPARδ has been demonstrated to suppress the generation of neurotoxic Aβ by attenuating BACE1 expression via the cytokine signaling 1-mediated inhibition of signal transducer and activator of transcription 1 signaling ( 60 ). In the present study, only the effects of ginsenoside Rg1 on PPARγ were observed.…”

Section: Discussionmentioning

confidence: 99%

Ginsenoside Rg1 promotes β‑amyloid peptide degradation through inhibition of the ERK/PPARγ phosphorylation pathway in an Alzheimer's disease neuronal model

Quan,

Ma,

et al. 2023

Exp Ther Med

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β-Amyloid peptide (Aβ) deposition in the brain is an important pathological change in Alzheimer's disease (AD). Insulin-degrading enzyme (IDE), which is regulated transcriptionally by peroxisome proliferator-activated receptor γ (PPARγ), is able to proteolyze Aβ. One of the members of the MAPK family, ERK, is able to mediate the phosphorylation of PPARγ at Ser112, thereby inhibiting its transcriptional activity. Ginsenoside Rg1 is one of the active ingredients in the natural medicine ginseng and has inhibitory effects on Aβ production. The present study was designed to investigate whether ginsenoside Rg1 is able to affect the regulation of PPARγ based on the expression of its target gene, IDE , and whether it is able to promote Aβ degradation via inhibition of the ERK/PPARγ phosphorylation pathway. In the present study, primary cultured rat hippocampal neurons were treated with Aβ 1-42 , ginsenoside Rg1 and the ERK inhibitor PD98059, and subsequently TUNEL staining was used to detect the level of neuronal apoptosis. ELISA was subsequently employed to detect the intra- and extracellular Aβ 1-42 levels, immunofluorescence staining and western blotting were used to detect the translocation of ERK from the cytoplasm to the nucleus, immunofluorescence double staining was used to detect the co-expression of ERK and PPARγ, and finally, western blotting was used to detect the phosphorylation of PPARγ at Ser112 and IDE expression. The results demonstrated that ginsenoside Rg1 or PD98059 were able to inhibit primary cultured hippocampal neuron apoptosis induced by Aβ 1-42 treatment, reduce the levels of intra- and extraneuronal Aβ 1-42 and inhibit the translocation of ERK from the cytoplasm to the nucleus. Furthermore, administration of ginsenoside Rg1 or PD98059 resulted in attenuated co-expression of ERK and PPARγ, inhibition of phosphorylation of PPARγ at Ser112 mediated by ERK and an increase in IDE expression. In addition, the effects when PD98059 to inhibit ERK followed by treatment with ginsenoside Rg1 were found to be more pronounced than those when using PD98059 alone. In conclusion, ginsenoside Rg1 was demonstrated to exert neuroprotective effects on AD via inhibition of the ERK/PPARγ phosphorylation pathway, which led to an increase in IDE expression, the promotion of Aβ degradation and the decrease of neuronal apoptosis. These results could provide a theoretical basis for the clinical application of ginsenoside Rg1 in AD.

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Section: Discussionmentioning

confidence: 99%

“…Our findings also evidence the enhanced transcription of two genes under the NFκB transcriptional control, that encode members of the STAT protein family of transcription factors (STAT1 and STAT5) and are involved in many aspects of cellular immunity, proliferation, apoptosis, and differentiation. 73 Moreover, STAT1 can regulate the expression of β secretase 1 for the generation of Aβ peptides, 74 while STAT5 seems to regulate microglial activation. 75 Apoptosis-modulating NFκB targets were also found overexpressed in the blood of the investigated AD patients, including the genes encoding the pro/anti-apoptotic Bcl-2like protein 1 (BCL2L1) and AKT1, as well as the apoptosis inducer Fas ligand (FASLG).…”

Section: Dovepressmentioning

confidence: 99%