The Therapeutic Prospects of Targeting IL-1R1 for the Modulation of Neuroinflammation in Central Nervous System Disorders

Luís, João; Simões, Carlos J. V.; Brito, Rui M. M.

doi:10.3390/ijms23031731

Cited by 29 publications

(14 citation statements)

References 257 publications

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“…The ORAI2 gene is a decisive factor in classifying AD samples as 0 and the gene 7981324 as 1 on frontal AD and non-AD samples, respectively. Figure 7 shows the SHAP interpretation on hippocampal AD and non-AD samples, identifying 8,015,796 and IL1RL2 (Luís et al 2022 ) as the top contributors to the predictions. The ORAI2 gene is found to have higher significance in a temporal dataset of both classes and stands on top of the other genes, as depicted in Fig.…”

Section: Resultsmentioning

confidence: 99%

Bioinformatics investigation on blood-based gene expressions of Alzheimer's disease revealed ORAI2 gene biomarker susceptibility: An explainable artificial intelligence-based approach

et al. 2023

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The progressive, chronic nature of Alzheimer's disease (AD), a form of dementia, defaces the adulthood of elderly individuals. The pathogenesis of the condition is primarily unascertained, turning the treatment efficacy more arduous. Therefore, understanding the genetic etiology of AD is essential to identifying targeted therapeutics. This study aimed to use machine-learning techniques of expressed genes in patients with AD to identify potential biomarkers that can be used for future therapy. The dataset is accessed from the Gene Expression Omnibus (GEO) database (Accession Number: GSE36980). The subgroups (AD blood samples from frontal, hippocampal, and temporal regions) are individually investigated against non-AD models. Prioritized gene cluster analyses are conducted with the STRING database. The candidate gene biomarkers were trained with various supervised machine-learning (ML) classification algorithms. The interpretation of the model prediction is perpetrated with explainable artificial intelligence (AI) techniques. This experiment revealed 34, 60, and 28 genes as target biomarkers of AD mapped from the frontal, hippocampal, and temporal regions. It is identified ORAI2 as a shared biomarker in all three areas strongly associated with AD's progression. The pathway analysis showed that STIM1 and TRPC3 are strongly associated with ORAI2. We found three hub genes, TPI1, STIM1, and TRPC3, in the network of the ORAI2 gene that might be involved in the molecular pathogenesis of AD. Naive Bayes classified the samples of different groups by fivefold cross-validation with 100% accuracy. AI and ML are promising tools in identifying disease-associated genes that will advance the field of targeted therapeutics against genetic diseases.

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Section: Resultsmentioning

confidence: 99%

Bioinformatics investigation on blood-based gene expressions of Alzheimer's disease revealed ORAI2 gene biomarker susceptibility: An explainable artificial intelligence-based approach

et al. 2023

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“…S100A9 activates NF-κB signaling and has been shown to aggravate neuroinflammation in a model of subarachnoid hemorrhage 108 and Alzheimer’s disease 109 and has been implicated as an integral component of inflammation along the gut-brain axis in the DSS model 15 . Cyclin-dependent kinase inhibitor p21, encoded by Cdkn1a , appears to be an inflammatory response element and may be a marker of DNA damage 110,111 , and an upregulation of the IL-1 receptor type 1, encoded by Il1r1 , has been associated with pathogenesis in several neurodegenerative diseases 112 . In general, the colitis-induced neuroimmune response is complex, and further work will be needed to unravel this complexity especially amidst LC injury.…”

Section: Discussionmentioning

confidence: 99%

Locus coeruleus injury modulates ventral midbrain neuroinflammation during DSS-induced colitis

Boles,

Holt,

Cole

et al. 2024

Preprint

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Parkinson's disease (PD) is characterized by a decades-long prodrome, consisting of a collection of non-motor symptoms that emerges prior to the motor manifestation of the disease. Of these non-motor symptoms, gastrointestinal dysfunction and deficits attributed to central norepinephrine (NE) loss, including mood changes and sleep disturbances, are frequent in the PD population and emerge early in the disease. Evidence is mounting that injury and inflammation in the gut and locus coeruleus (LC), respectively, underlie these symptoms, and the injury of these systems is central to the progression of PD. In this study, we generate a novel two-hit mouse model that captures both features, using dextran sulfate sodium (DSS) to induce gut inflammation and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) to lesion the LC. We first confirmed the specificity of DSP-4 for central NE using neurochemical methods and fluorescence light-sheet microscopy of cleared tissue, and established that DSS-induced outcomes in the periphery, including weight loss, gross indices of gut injury and systemic inflammation, the loss of tight junction proteins in the colonic epithelium, and markers of colonic inflammation, were unaffected with DSP-4 pre-administration. We then measured alterations in neuroimmune gene expression in the ventral midbrain in response to DSS treatment alone as well as the extent to which prior LC injury modified this response. In this two-hit model we observed that DSS-induced colitis activates the expression of key cytokines and chemokines in the ventral midbrain only in the presence of LC injury and the typical DSS-associated neuroimmune is blunted by pre-LC lesioning with DSP-4. In all, this study supports the growing appreciation for the LC as neuroprotective against inflammation-induced brain injury and draws attention to the potential for NEergic interventions to exert disease-modifying effects under conditions where peripheral inflammation may compromise ventral midbrain dopaminergic neurons and increase the risk for development of PD.

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“… 86 , 87 IL1R1, a member of the interleukin-1 family, plays a central role in the pro-inflammatory response seen in sporadic AD and various other diseases. 88 , 89 …”

Section: Discussionmentioning

confidence: 99%

CSF proteomics in autosomal dominant Alzheimer’s disease highlights parallels with sporadic disease

van der Ende,

In ‘t Veld,

Hanskamp

et al. 2023

Brain

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Autosomal dominant Alzheimer’s disease (ADAD) offers a unique opportunity to study pathophysiological changes in a relatively young population with few comorbidities. A comprehensive investigation of proteome changes occurring in ADAD could provide valuable insights into AD-related biological mechanisms and uncover novel biomarkers and therapeutic targets. Furthermore, ADAD might serve as a model for sporadic AD, but in-depth proteome comparisons are lacking. We aimed to identify dysregulated CSF proteins in ADAD and determine the degree of overlap with sporadic AD. We measured 1472 proteins in CSF of PSEN1 or APP mutation carriers (n = 22) and age- and sex-matched controls (n = 20) from the Amsterdam Dementia Cohort using proximity extension-based immunoassays (PEA) by Olink. We compared protein abundance between groups with two-sided t-tests and identified enriched biological pathways. Using the same protein panels in paired plasma samples, we investigated correlations between CSF proteins and their plasma counterparts. Finally, we compared our results with recently published PEA data from an international cohort of sporadic AD (n = 230) and non-AD dementias (n = 301). All statistical analyses were false discovery rate-corrected. We detected 66 differentially abundant CSF proteins (65 increased, one decreased) in ADAD compared to controls (q < 0.05). The most strongly upregulated proteins (fold change >1.8) were related to immunity (CHIT1, ITGB2, SMOC2), cytoskeletal structure (MAPT, NEFL) and tissue remodeling (TMSB10, MMP-10). Significant CSF-plasma correlations were found for the upregulated proteins SMOC2 and LILR1B. 36 of the 66 differentially expressed proteins had been previously measured in the sporadic dementias cohort, 34 of which (94%) were also significantly upregulated in sporadic AD, with a strong correlation between the fold changes of these proteins in both cohorts (rs = 0.730, p < 0.001). 29 of these 36 proteins (81%) were also upregulated among non-AD patients with suspected AD co-pathology. This CSF proteomics study demonstrates substantial biochemical similarities between ADAD and sporadic AD, suggesting involvement of the same biological processes. Besides known AD-related proteins, we identified several relatively novel proteins, such as TMSB10, MMP-10 and SMOC2, which have potential as novel biomarkers. With shared pathophysiological CSF changes, ADAD study findings might be translatable to sporadic AD, which could greatly expedite therapy development.

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The Therapeutic Prospects of Targeting IL-1R1 for the Modulation of Neuroinflammation in Central Nervous System Disorders

Cited by 29 publications

References 257 publications

Bioinformatics investigation on blood-based gene expressions of Alzheimer's disease revealed ORAI2 gene biomarker susceptibility: An explainable artificial intelligence-based approach

Bioinformatics investigation on blood-based gene expressions of Alzheimer's disease revealed ORAI2 gene biomarker susceptibility: An explainable artificial intelligence-based approach

Locus coeruleus injury modulates ventral midbrain neuroinflammation during DSS-induced colitis

CSF proteomics in autosomal dominant Alzheimer’s disease highlights parallels with sporadic disease

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