Figure
RIG-1 is elevated in the plasma of mild cognitive impairment (MCI) patients. Representative immunoblots (A) of plasma (B) and serum (C) from age-matched controls (NCI), MCI and Alzheimer Disease (AD) patients analyzed for RIG-1 expression. 5 μg of protein were loaded for the plasma and serum samples after removal of IgG. Data presented as mean ± SEM. *P < 0.05. N = NCI: 6, MCI: 7 and AD: 10 patients.
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Neuroinflammation plays a critical role in the pathogenesis of Alzheimer's disease (AD) and involves activation of the innate immune response via recognition of diverse stimuli by pattern recognition receptors (PRRs). The inflammatory inducers and precise innate signaling pathway contributing to AD pathology remain largely undefined.
In the present...
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Context 1
... determine the levels of RIG-1 in the plasma and serum of patients with MCI associated with AD, im- munoglobulin G was isolated from serum and plasma obtained from patients corresponding to the NCI, MCI and AD groups, as described above. Figure 2 shows that RIG-1 was significantly increased in the plasma ( Figure 2B) from MCI patients compared to the NCI and AD groups, whereas the levels of RIG-1 in serum ( Figure 2C) did not differ among the three groups. Thus, these results show for the first time that RIG-1 is in- creased in the plasma of MCI patients. ...Context 2
... determine the levels of RIG-1 in the plasma and serum of patients with MCI associated with AD, im- munoglobulin G was isolated from serum and plasma obtained from patients corresponding to the NCI, MCI and AD groups, as described above. Figure 2 shows that RIG-1 was significantly increased in the plasma ( Figure 2B) from MCI patients compared to the NCI and AD groups, whereas the levels of RIG-1 in serum ( Figure 2C) did not differ among the three groups. Thus, these results show for the first time that RIG-1 is in- creased in the plasma of MCI patients. ...Context 3
... determine the levels of RIG-1 in the plasma and serum of patients with MCI associated with AD, im- munoglobulin G was isolated from serum and plasma obtained from patients corresponding to the NCI, MCI and AD groups, as described above. Figure 2 shows that RIG-1 was significantly increased in the plasma ( Figure 2B) from MCI patients compared to the NCI and AD groups, whereas the levels of RIG-1 in serum ( Figure 2C) did not differ among the three groups. Thus, these results show for the first time that RIG-1 is in- creased in the plasma of MCI patients. ...Similar publications
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Citations
... Furthermore, these results suggest ASC is a promising biomarker for early detection of cognitive impairment. This finding is consistent with other studies that showed inflammatory proteins such as RIG-I [59] and TREM2 [60] to be elevated early in the stages of cognitive decline and then decreased in the later stages. These findings suggest that the pattern of expression in which a protein is upregulated in the early stages of cognitive decline followed by downregulation in the later stages is perhaps characteristic of inflammation-associated proteins. ...
Dementia is a group of symptoms including memory loss, language difficulties, and other types of cognitive and functional impairments that affects 57 million people worldwide, with the incidence expected to double by 2040. Therefore, there is an unmet need to develop reliable biomarkers to diagnose early brain impairments so that emerging interventions can be applied before brain degeneration. Here, we performed biomarker analyses for apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and amyloid-β 42/40 (Aβ42/40) ratio in the plasma of older adults. Participants had blood drawn at baseline and underwent two annual clinical and cognitive evaluations. The groups tested either cognitively normal on both evaluations (NN), cognitively normal year 1 but cognitively impaired year 2 (NI), or cognitively impaired on both evaluations (II). ASC was elevated in the plasma of the NI group compared to the NN and II groups. Additionally, Aβ42 was increased in the plasma in the NI and II groups compared to the NN group. Importantly, the area under the curve (AUC) for ASC in participants older than 70 years old in NN vs. NI groups was 0.81, indicating that ASC is a promising plasma biomarker for early detection of cognitive decline.
... Finally, one upregulated gene named ISG15 was predicted to be involved in RIG-I-like receptor signaling pathway which may lead to the inflammatory response through the activation of type I IFN production in AD [44]. Additionally, two downregulated genes such as TTR and LTF in AD were predicted to be involved in thyroid hormone synthesis, amyloid fiber formation, diseases associated with visual transduction, neutrophil degranulation, and canonical retinoid cycle in rods (Twilight Vision) pathways. ...
Alzheimer's disease (AD) poses a major challenge due to its impact on the elderly population and the lack of effective early diagnosis and treatment options. In an effort to address this issue, a study focused on identifying potential biomarkers and therapeutic agents for AD was carried out. Using RNA-Seq data from AD patients and healthy individuals, 12 differentially expressed genes (DEGs) were identified, with 9 expressing upregulation (ISG15, HRNR, MTATP8P1, MTCO3P12, DTHD1, DCX, ST8SIA2, NNAT, and PCDH11Y) and 3 expressing downregulation (LTF, XIST, and TTR). Among them, TTR exhibited the lowest gene expression profile. Interestingly, functional analysis tied TTR to amyloid fiber formation and neutrophil degranulation through enrichment analysis. These findings suggested the potential of TTR as a diagnostic biomarker for AD. Additionally, druggability analysis revealed that the FDA-approved drug Levothyroxine might be effective against the Transthyretin protein encoded by the TTR gene. Molecular docking and dynamics simulation studies of Levothyroxine and Transthyretin suggested that this drug could be repurposed to treat AD. However, additional studies using in vitro and in vivo models are necessary before these findings can be applied in clinical applications.
... Our selection is based on a combination of the resulting enrichment score and the existing knowledge supporting a possible relation with the nervous system function. Therefore, through the neurons analysis (Additional file 8), "interferon signaling" and "RIG-I-like receptor signaling" have been the topscored Reactome 2016 and KEGG 2019 pathways respectively, suggesting that neuroinflammation might play an important role in the pathogenesis of SA similarly to other neurodegenerative diseases, such as AD [83], FRDA [84,85] and ALS [86,87] or it may even be the reaction of the cells to the altered function of GBA2. In addition, RIG-I signaling has been found significantly increased in the plasma and temporal cortex of mild cognitive impairment patients with AD, as well as in the occipital cortex of AD patients. ...
... In addition, RIG-I signaling has been found significantly increased in the plasma and temporal cortex of mild cognitive impairment patients with AD, as well as in the occipital cortex of AD patients. Elevation of RIG-I can be caused by small self-RNA cleavage products or by ROS, which are in turn associated with oxidative stress [83]. ...
Background
Spastic ataxias (SAs) encompass a group of rare and severe neurodegenerative diseases, characterized by an overlap between ataxia and spastic paraplegia clinical features. They have been associated with pathogenic variants in a number of genes, including GBA2 . This gene codes for the non-lysososomal β-glucosylceramidase, which is involved in sphingolipid metabolism through its catalytic role in the degradation of glucosylceramide. However, the mechanism by which GBA2 variants lead to the development of SA is still unclear.
Methods
In this work, we perform next-generation RNA-sequencing (RNA-seq), in an attempt to discover differentially expressed genes (DEGs) in lymphoblastoid, fibroblast cell lines and induced pluripotent stem cell-derived neurons derived from patients with SA, homozygous for the GBA2 c.1780G > C missense variant. We further exploit DEGs in pathway analyses in order to elucidate candidate molecular mechanisms that are implicated in the development of the GBA2 gene-associated SA.
Results
Our data reveal a total of 5217 genes with significantly altered expression between patient and control tested tissues. Furthermore, the most significant extracted pathways are presented and discussed for their possible role in the pathogenesis of the disease. Among them are the oxidative stress, neuroinflammation, sphingolipid signaling and metabolism, PI3K-Akt and MAPK signaling pathways.
Conclusions
Overall, our work examines for the first time the transcriptome profiles of GBA2 -associated SA patients and suggests pathways and pathway synergies that could possibly have a role in SA pathogenesis. Lastly, it provides a list of DEGs and pathways that could be further validated towards the discovery of disease biomarkers.
... Furthermore, a network-based analysis of Alzheimer's using cerebellum astrocyte cells and Thalassemia disease using the erythroid progenitor cells was also performed (Supplementary Figure 3). Few pathways predicted by Bayesian modelling appeared relevant for Alzheimer's disease, such as retinoic acid-inducible gene-I (RIG-I)-mediated IFN alpha-beta [50] and PPAR pathways [51] ( Figure 3C). For thalassemia disease, few associated pathways predicted by Bayesian modelling were relevant such as FGFR signalling [52] and erythrocyte membrane transport [53] (Figure 3D). ...
Finding direct dependencies between genetic pathways and diseases has been the target of multiple studies as it has many applications. However, due to cellular heterogeneity and limitations of the number of samples for bulk expression profiles, such studies have faced hurdles in the past. Here, we propose a method to perform single-cell expression-based inference of association between pathway, disease and cell-type (sci-PDC), which can help to understand their cause and effect and guide precision therapy. Our approach highlighted reliable relationships between a few diseases and pathways. Using the example of diabetes, we have demonstrated how sci-PDC helps in tracking variation of association between pathways and diseases with changes in age and species. The variation in pathways-disease associations in mice and humans revealed critical facts about the suitability of the mouse model for a few pathways in the context of diabetes. The coherence between results from our method and previous reports, including information about the drug target pathways, highlights its reliability for multidimensional utility.
... These results highlight the importance of TLRs in driving AD pathology. Involved in the pathology of MCI associated with early progression to AD [94] Other PRRs, such as inflammasome sensors, have also been associated with AD. Inflammasomes are multiprotein complexes that form in response to PAMP or DAMP sensing, and they generally contain a sensor, the adaptor protein ASC, and caspase-1. ...
... Nucleic acid-containing Aβ elicits a Cells 2022, 11, 1885 7 of 25 TLR-and RLR-derived type I IFN response for C3-dependent synapse destruction [106]. The expression of RIG-I, a key member of the RLR family, is elevated in the temporal cortex and plasma of patients with cognitive impairment [94]. However, the mechanistic details of RIG-I involvement in AD pathogenesis have yet to be discovered. ...
... The major pathological hallmarks of AD include extracellular Aβ deposition, the intraneuronal aggregation of NFTs, and neuronal loss (neurodegeneration) [129]. In mammalian hosts, Aβ and Tau deposits act as DAMPs and are recognized by multiple PRRs, as discussed above [68,88,94,130,131] (Table 2). The subsequent innate immune signaling can result in cell death, and these processes can provide significant protective responses against AD [62,88,131]. ...
Alzheimer’s disease (AD) is a neurodegenerative disorder molecularly characterized by the formation of amyloid β (Aβ) plaques and type 2 microtubule-associated protein (Tau) abnormalities. Multiple studies have shown that many of the brain’s immunological cells, specifically microglia and astrocytes, are involved in AD pathogenesis. Cells of the innate immune system play an essential role in eliminating pathogens but also regulate brain homeostasis and AD. When activated, innate immune cells can cause programmed cell death through multiple pathways, including pyroptosis, apoptosis, necroptosis, and PANoptosis. The cell death often results in the release of proinflammatory cytokines that propagate the innate immune response and can eliminate Aβ plaques and aggregated Tau proteins. However, chronic neuroinflammation, which can result from cell death, has been linked to neurodegenerative diseases and can worsen AD. Therefore, the innate immune response must be tightly balanced to appropriately clear these AD-related structural abnormalities without inducing chronic neuroinflammation. In this review, we discuss neuroinflammation, innate immune responses, inflammatory cell death pathways, and cytokine secretion as they relate to AD. Therapeutic strategies targeting these innate immune cell death mechanisms will be critical to consider for future preventive or palliative treatments for AD.
... As a sensor, RIG-I detects 5'-PPP double-stranded RNAs produced by a variety of viruses and intracellular bacteria. Therefore, RIG-I is responsible for mounting a response against infectious agents besides partaking in neuroinflammatory processes linked with neurodegenerative diseases [293,294]. ...
... Moreover, an exposure to the RIG-1 ligand 5'ppp RNA increased the expression of APP and Aβs in primary human astrocytes. These results have revealed a potential implication of RIG-1 in the MCI phase of AD development [294]. ...
Fibrillar aggregates and soluble oligomers of both Amyloid-β peptides (Aβs) and hyperphosphorylated Tau proteins (p-Tau-es), as well as a chronic neuroinflammation are the main drivers causing progressive neuronal losses and dementia in Alzheimer’s disease (AD). However, the underlying pathogenetic mechanisms are still much disputed. Several endogenous neurotoxic ligands, including Aβs, and/or p-Tau-es activate innate immunity-related danger-sensing/pattern recognition receptors (PPRs) thereby advancing AD’s neuroinflammation and progression. The major PRR families involved include scavenger, Toll-like, NOD-like, AIM2-like, RIG-like, and CLEC-2 receptors, plus the calcium-sensing receptor (CaSR). This quite intricate picture stresses the need to identify the pathogenetically topmost Aβ-activated PRR, whose signaling would trigger AD’s three main drivers and their intra-brain spread. In theory, the candidate might belong to any PRR family. However, results of preclinical studies using in vitro nontumorigenic human cortical neurons and astrocytes and in vivo AD-model animals have started converging on the CaSR as the pathogenetically upmost PRR candidate. In fact, the CaSR binds both Ca²⁺ and Aβs and promotes the spread of both Ca²⁺ dyshomeostasis and AD’s three main drivers, causing a progressive neurons’ death. Since CaSR’s negative allosteric modulators block all these effects, CaSR’s candidacy for topmost pathogenetic PRR has assumed a growing therapeutic potential worth clinical testing.
... Another gene related to IFN response, DDX58 and IFIH1 were found upregulated and of which DDX58 encode an RIG-I-like receptor dsRNA that recognized viral double stranded RNA (Yoneyama et al., 2004). It initiates immune response through mitochondrial antiviral signaling and shown to be associated with neuroinflammation (de Rivero Vaccari et al., 2014;MacNair et al., 2016). Upregulation of DDX58 and IFIH1 in SCA12 suggest that mechanism of neurodegeneration could be a consequence of inflammation that is activated through the RIG1 signaling in response to over expression of RNA. ...
Spinocerebellar ataxia type-12 (SCA12) is a neurological disorder that exhibits a unique progressive tremor/ataxia syndrome induced by triplet (CAG) repeat expansion in 5’ UTR of PPP2R2B . SCA12 is one of the most prominent SCA-subtype in India and till date no appropriate disease models have been described. Our aim was to establish human iPSC derived neuronal cell lines of SCA12 and study transcriptomic level alterations induced by CAG expansion. For translational application, peripheral blood transcriptomics of SCA12 patients was also performed. Lymphoblastoid cell lines of three SCA12 patients were reprogrammed to iPSCs and then re-differentiated into pan-neuronal lineage. RNA-sequencing based comparative transcriptomics was performed for disease and control cell lineages. Microarray based transcriptomic profiling of peripheral blood of SCA12 patients was performed in a case/control (n=15/9) design. We have successfully created human neuronal cell lines of SCA12 patient as exhibited by their molecular profiling. Differential expression analysis of RNA-Seq data has shown enrichment for type-I interferon signaling and other relevant cellular processes in SCA12-neurons. At the splice-isoform level, we observed an upregulation of expanded CAG containing non-coding transcript of PPP2R2B . Peripheral blood transcriptomics analysis and targeted validation of RNA-Seq data has allowed us to identify inflammatory signatures as potential markers of molecular pathology in SCA12. Our study has allowed us to establish first iPSC based neuronal cell lines of SCA12. We have identified pro-inflammatory signatures in SCA12-neurons suggestive of a dsRNA mediated activation of interferon signaling and that corroborates with the emerging evidence of neuronal atrophy due to neuro-inflammation in common neurodegenerative diseases. This study involved development of an iPSCs derived neuronal cells of SCA12 and look through signatures of neurodegeneration by whole RNA sequencing. This model sheds light upon key role of RNA mediated induced response in Interferon signaling for neurodegeneration.
... In our study, we found that DDX58 was clearly downregulated, which inferred that abnormal accumulations of TDP-43 in HD could be responsible for this result. Other studies also found that DDX58 was involved in immune regulation (36). HERC6 is a HerC protein family member; a previous study found that HERC6 was the main E3 ligase for global ISG15 conjugation in mouse cells (37). ...
Huntington's disease (HD) is an inherited, progressive neurodegenerative disease caused by a CAG expansion in the huntingtin (HTT) gene; various dysfunctions of biological processes in HD have been proposed. However, at present the exact pathogenesis of HD is not fully understood. The present study aimed to explore the pathogenesis of HD using a computational bioinformatics analysis of gene expression. GSE11358 was downloaded from the Gene Expression Omnibus andthe differentially expressed genes (DEGs) in the mutant HTT knock‑in cell model STHdhQ111/Q111 were predicted. DEGs between the HD and control samples were screened using the limma package in R. Functional and pathway enrichment analyses were conducted using the database for annotation, visualization and integrated discovery software. A protein‑protein interaction (PPI) network was established by the search tool for the retrieval of interacting genes and visualized by Cytoscape. Module analysis of the PPI network was performed utilizing MCODE. A total of 471 DEGs were identified, including ribonuclease A family member 4 (RNASE4). In addition, 41 significantly enriched Kyoto Encyclopedia of Genes and Genomes pathways, as well as several significant Gene Ontology terms (including cytokine‑cytokine receptor interaction and cytosolic DNA‑sensing) were identified. A total of 18 significant modules were identified from the PPI network. Furthermore, a novel transcriptional regulatory relationship was identified, namely signal transducer and activator of transcription 3 (STAT3), which is regulated by miRNA‑124 in HD. In conclusion, deregulation of 18 critical genes may contribute to the occurrence of HD. RNASE4, STAT3, and miRNA‑124 may have a regulatory association with the pathological mechanisms in HD.
... Moreover, extracellular OAS2 was documented to be capable of down-regulating the T-cell receptor chain (CD3-ζ) via caspase-3 activation, thereby contributing to a decrease in T-cell responsiveness [54]. The plasma level of RIG-1, as an RNase-L downstream molecule, were found to be higher in patients with mild cognitive impairment, suggesting that extracellular RIG-1 level may be involved in the incipient neurodegenerative disorders, such as Alzheimer's disease [55]. In this study, we reported the presence of RNase-L in human serum and analyzed its relation with MetS, but the functions of these antiviral proteins in extracellular compartment remain unclear. ...
Background
Ribonuclease-L (RNase-L) was known to be a ubiquitous enzyme involved in several cellular functions, especially innate immunity. It was recently shown to participate in adipogenesis in rodents. Here, we developed a method to measure serum levels of RNase-L and analyzed the relationship between RNase-L and metabolic syndrome (MetS). MethodsA total of 396 subjects were recruited from a health check-up program. An in-house RNase-L immunoassay was developed. The serum RNase-L levels of these subjects were measured, and the association of MetS-related factors with RNase-L levels was assessed. ResultsThe mean serum level of RNase-L of the subjects with MetS were lower than those without (16.5 ± 6.4 vs. 18.4 ± 8.0 μg/ml, P = 0.018). The subjects with central obesity, elevated blood pressure, or impaired fasting glucose also had lower serum RNase-L levels in comparison to those without. In multivariate linear regression analysis, diastolic blood pressure (β = −0.129, P = 0.024) and high-density lipoprotein cholesterol (HDL-C) (β = 0.127, P = 0.036) were related to serum RNase-L. For every 5 μg/ml increase in serum RNase-L levels, it is associated with a reduced risk of MetS (OR 0.83, 95% CI 0.71–0.98, P = 0.028), central obesity (OR 0.82, 95% CI 0.71–0.94, P = 0.005), or low HDL-C (OR 0.86, 95% CI 0.74–1.00, P = 0.042). Moreover, age is inversely related to serum RNase-L levels in various analyses. Conclusions
The serum RNase-L levels were inversely associated with MetS, unfavorable metabolic profiles, and age.
... Additionally, RIG-1 activates interferon regulatory factors (IRFs) which transcribes from type 1 interferons (IFN-Is). 11 IFN-Is are important cytokines which interfere with brain functions in several disorders such as multiple sclerosis and Alzheimer. 11 It is also proposed that the elevated levels of RIG-1 in the female T2D patients with bad orgasm is related to the increased expression of IFN-Is and their Several studies have demonstrated the role of inflammation in the induction of bad orgasm in the females. ...
... 11 IFN-Is are important cytokines which interfere with brain functions in several disorders such as multiple sclerosis and Alzheimer. 11 It is also proposed that the elevated levels of RIG-1 in the female T2D patients with bad orgasm is related to the increased expression of IFN-Is and their Several studies have demonstrated the role of inflammation in the induction of bad orgasm in the females. 12 Additionally, mental disorders are the main causes of sexual malfunctions in the female T2D patients 13,14 ; therefore, due to high prevalence of mental disorders in the patients, it has been hypothesized that the mental disorders are the main causes of sexual malfunctions in the female T2D patients. ...
Introduction: The patients with type 2 diabetes (T2D) suffer from the malfunctions of the sexual behaviors, and several mechanisms have been proposed to describe these disorders. The innate immunity may be involved in the malfunctions of T2D patients. Melanoma differentiation-associated protein 5 (MDA5) and retinoic acid (RA)-inducible gene 1 (RIG-1), as the innate immunity receptors, are the responsible molecules for the activation of some intracellular signaling pathways and the induction of inflammation. Thus, this study aimed to examine the molecules which may participate in the induction/stimulation of sexual malfunctions in the female T2D patients.
Methods: Sexual functions were evaluated in 41 female T2D patients using the Female Sexual Function Index (FSFI) questionnaire. Real-time polymerase chain reaction (PCR) technique was used to quantify MDA5 and RIG-1 mRNA levels.
Results: Results showed that increased RIG-1 mRNA levels were significantly associated with the bad orgasm in the female T2D patients compared to the female patients with good orgasm. Expression of RIG-1 and MDA5 levels were not associated with other sexual functions’ criteria.
Conclusion: The findings of this study demonstrated that bad orgasm is associated with the increased RIG-1 expression. Consequently, the correlation between inflammation and bad orgasm in a RIG-1 dependent manner is suggested.
