lncRNA XIST induces Aβ accumulation and neuroinflammation by the epigenetic repression of NEP in Alzheimer’s disease

Yan, Xiwu; Liu, Huaijun; Hong, Yu-Xing; Meng, Ting; Du, Jun; Chang, Cheng

doi:10.1080/01677063.2022.2028784

Cited by 23 publications

(23 citation statements)

References 43 publications

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“…XIST codes for long non-coding RNA Xist , X inactive specific transcript, which is involved in the inactivation of one X chromosome in females [ 52 ]. XIST has been implicated in neuropsychiatric disorders [ 53 ] and LOAD [ 54 , 55 , 56 ], to which our results provide additional support.…”

Section: Discussionsupporting

confidence: 76%

Differential Gene Expression and DNA Methylation in the Risk of Depression in LOAD Patients

et al. 2022

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Depression is common among late-onset Alzheimer’s Disease (LOAD) patients. Only a few studies investigated the genetic variability underlying the comorbidity of depression in LOAD. Moreover, the epigenetic and transcriptomic factors that may contribute to comorbid depression in LOAD have yet to be studied. Using transcriptomic and DNA-methylomic datasets from the ROSMAP cohorts, we investigated differential gene expression and DNA-methylation in LOAD patients with and without comorbid depression. Differential expression analysis did not reveal significant association between differences in gene expression and the risk of depression in LOAD. Upon sex-stratification, we identified 25 differential expressed genes (DEG) in males, of which CHI3L2 showed the strongest upregulation, and only 3 DEGs in females. Additionally, testing differences in DNA-methylation found significant hypomethylation of CpG (cg20442550) on chromosome 17 (log2FC = −0.500, p = 0.004). Sex-stratified differential DNA-methylation analysis did not identify any significant CpG probes. Integrating the transcriptomic and DNA-methylomic datasets did not discover relationships underlying the comorbidity of depression and LOAD. Overall, our study is the first multi-omics genome-wide exploration of the role of gene expression and epigenome alterations in the risk of comorbid depression in LOAD patients. Furthermore, we discovered sex-specific differences in gene expression underlying the risk of depression symptoms in LOAD.

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Section: Discussionsupporting

confidence: 76%

Differential Gene Expression and DNA Methylation in the Risk of Depression in LOAD Patients

et al. 2022

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“…It is well recognized that Aβ is the toxic species in AD and can induce neuron death ( Akhter et al, 2014 ). Aβ accumulation can further aggravate neuroinflammation and lead to neuronal injury, which indicates that the reduction of Aβ accumulation is vital in reducing neuroinflammation, neuronal injury and death ( Yan et al, 2022 ). KEGG enrichment analysis showed that the pathways related to inflammation and immunity, such as PI3K-Akt, TNF, IL-17 signaling pathways were correlated with the specific mechanism of QZZD in the treatment of AD.…”

Section: Discussionmentioning

confidence: 99%

Network pharmacology analysis reveals neuroprotective effects of the Qin-Zhi-Zhu-Dan Formula in Alzheimer’s disease

Ren

Zhang

et al. 2022

Front. Neurosci.

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There is yet no effective drug for Alzheimer’s disease (AD) which is one of the world’s most common neurodegenerative diseases. The Qin-Zhi-Zhu-Dan Formula (QZZD) is derived from a widely used Chinese patent drug–Qing-Kai-Ling Injection. It consists of Radix Scutellariae, Fructus Gardeniae, and Pulvis Fellis Suis. Recent study showed that QZZD and its effective components played important roles in anti-inflammation, antioxidative stress and preventing brain injury. It was noted that QZZD had protective effects on the brain, but the mechanism remained unclear. This study aims to investigate the mechanism of QZZD in the treatment of AD combining network pharmacology approach with experimental validation. In the network pharmacology analysis, a total of 15 active compounds of QZZD and 135 putative targets against AD were first obtained. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were then applied to clarify the biological mechanism. The anti-inflammatory mechanism of QZZD was proved, and a synthetic pathway–TNFR1-ERK1/2-NF-κBp65 signaling pathway was obtained. On the basis of the above discoveries, we further validated the protective effects QZZD on neurons with an APP/PS1 double transgenic mouse model. Weight change of the mice was monitored to assess QZZD’s influence on the digestive system; water maze experiment was used for evaluating the effects on spatial learning and memory; Western blotting and immunohistochemistry analysis were used to detect the predicted key proteins in network pharmacology analysis, including Aβ, IL-6, NF-κBp65, TNFR1, p-ERK1/2, and ERK1/2. We proved that QZZD could improve neuroinflammation and attenuate neuronal death without influencing the digestive system in APP/PS1 double transgenic mice with dementia. Combining animal pharmacodynamic experiments with network pharmacology analysis, we confirmed the importance of inflammation in pathogenesis of AD, clarified the pharmacodynamic characteristics of QZZD in treating AD, and proved its neuroprotective effects through the regulation of TNFR1-ERK1/2-NF-κBp65 signaling pathway, which might provide reference for studies on treatment of AD in the future.

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“…AD involves the accumulation of β-amyloid (Aβ) peptide, which is a cleavage product of the amyloid precursor protein (APP). Xist expression was significantly upregulated in AD mice and cell models, 176 , 177 where inflammation and injury of nerve cells occurred. 177 Xist is a molecular sponge of miR-124 that targets BACE1 , an enzyme crucial for the cleavage of APP and serving as a biomarker of AD.…”

Section: Xist and Sex-biased Diseasesmentioning

confidence: 99%

“…Xist expression was significantly upregulated in AD mice and cell models, 176 , 177 where inflammation and injury of nerve cells occurred. 177 Xist is a molecular sponge of miR-124 that targets BACE1 , an enzyme crucial for the cleavage of APP and serving as a biomarker of AD. Xist silencing could reduce BACE1 expression through miR-124.…”

Section: Xist and Sex-biased Diseasesmentioning

confidence: 99%

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Long noncoding RNA XIST: Mechanisms for X chromosome inactivation, roles in sex-biased diseases, and therapeutic opportunities

Zhe

Yang

et al. 2022

Genes & Diseases

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lncRNA XIST induces Aβ accumulation and neuroinflammation by the epigenetic repression of NEP in Alzheimer’s disease

Cited by 23 publications

References 43 publications

Differential Gene Expression and DNA Methylation in the Risk of Depression in LOAD Patients

Differential Gene Expression and DNA Methylation in the Risk of Depression in LOAD Patients

Network pharmacology analysis reveals neuroprotective effects of the Qin-Zhi-Zhu-Dan Formula in Alzheimer’s disease

Long noncoding RNA XIST: Mechanisms for X chromosome inactivation, roles in sex-biased diseases, and therapeutic opportunities

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