Inhibition of IFITM3 in cerebrovascular endothelium alleviates Alzheimer's‐related phenotypes

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 14, 2025

Abstract INTRODUCTION Interferon‐induced transmembrane protein 3 (IFITM3) modulates γ‐secretase in Alzheimer's Disease (AD). Although IFITM3 knockout reduces amyloid β (Aβ) production, its cell‐specific effect on AD remains unclear. METHODS Single nucleus RNA sequencing (snRNA‐seq) was used to assess expression. Adeno‐associated virus‐BI30 (AAV‐BI30) injected reduce expression the cerebrovascular endothelial cells (CVECs). The effects phenotypes and mice were examined through behavioral tests, two‐photon imaging, flow cytometry, Western blot, immunohistochemistry, quantitative polymerase chain reaction assay (qPCR). RESULTS increased CVECs of patients with AD. Overexpression primary enhanced Aβ generation regulating beta‐site APP cleaving enzyme 1 (BACE1) γ‐secretase. further expression, creating a vicious cycle. Knockdown decreased accumulation within walls, reduced Alzheimer's‐related pathology, improved cognitive performance transgenic mice. DISCUSSION alleviates pathology impairment. Targeting holds promise for treatment. Highlights ( ) (CVECs) Cerebrovascular regulates deposits improves impairments could be potential target treatment

Language: Английский

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A Review of the Therapeutic Potential of Sulfur Compounds in Allium sativum

Measurement Food, Journal Year: 2024, Volume and Issue: 15, P. 100195 - 100195

Published: Aug. 28, 2024

Language: Английский

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Viral infections of the central nervous system increase the risk of knee osteoarthritis: a two-sample mendelian randomization study

Aging Clinical and Experimental Research, Journal Year: 2025, Volume and Issue: 37(1)

Published: Jan. 21, 2025

Abstract Objective Osteoarthritis (OA) represents a condition under the influence of central nervous system (CNS) regulatory mechanisms. This investigation aims to examine causal association between viral infections (VICNS) and inflammatory diseases (IDCNS) knee osteoarthritis (KOA) at genetic level. Methods In this investigation, VICNS IDCNS were considered as primary exposure variables, while KOA served outcome. Employing two-sample mendelian randomization (MR) approach, we conducted an analysis utilizing summary data derived from genome-wide studies (GWAS). The GWAS pertaining procured Finnish consortium, whereas IEU OpenGWAS database furnished requisite for KOA. To ensure robustness our assessment, comprehensive array sensitivity analyses was undertaken, encompassing evaluations heterogeneity, horizontal pleiotropy, outlier identification, leave-one-out analyses, assessment normal distribution. Results results MR revealed suggestive positive relationship ( P = 0.012, odds ratio [OR] with 95% confidence interval [CI] 1.033 [1.007–1.059]). Conversely, did not indicate any evidence causation 0.575, OR CI 0.986 [0.940–1.035]). Importantly, outcome variables demonstrate indications or outliers. Furthermore, remained robust against individual single nucleotide polymorphisms (SNPs) exhibited adherence Conclusion result study has elucidated link However, no such observed These findings substantiate underpinnings supporting CNS OA.

Language: Английский

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Unveiling the role of KLF9‐mediated IFITM3 regulation in amyloidogenesis

The FASEB Journal, Journal Year: 2025, Volume and Issue: 39(4)

Published: Feb. 14, 2025

Abstract Interferon‐induced transmembrane protein 3 (IFITM3) is implicated in the pathogenesis of Alzheimer's Disease (AD) by regulating γ‐secretase activity and subsequent amyloid β (Aβ) generation. However, regulation IFITM3 gene expression underlying mechanisms remain exclusive. In this study, we aimed to investigate its role amyloidogenesis. The functional active promoter was identified within 1047 bp 5′‐flanking regions luciferase assays. Through chromatin immunoprecipitation (ChIP) electrophoretic mobility shift assay (EMSA), successfully a specific Krüppel‐like factor 9 (KLF9) binding site region. Moreover, KLF9 overexpression significantly upregulates vitro vivo, which promotes Aβ generation hippocampus mice. Consistently, reduced results notable decrease production. Together, demonstrate that plays critical It highly suggests inhibiting KLF9‐mediated may have therapeutic potential for AD reducing

Language: Английский

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Virus-Induced Epilepsy vs. Epilepsy Patients Acquiring Viral Infection: Unravelling the Complex Relationship for Precision Treatment

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(7), P. 3730 - 3730

Published: March 27, 2024

The intricate relationship between viruses and epilepsy involves a bidirectional interaction. Certain can induce by infecting the brain, leading to inflammation, damage, or abnormal electrical activity. Conversely, patients may be more susceptible viral infections due factors, such as compromised immune systems, anticonvulsant drugs, surgical interventions. Neuroinflammation, common factor in both scenarios, exhibits onset, duration, intensity, consequence variations. It modulate epileptogenesis, increase seizure susceptibility, impact drug pharmacokinetics, system function, brain physiology. Viral significantly clinical management of patients, necessitating multidisciplinary approach encompassing diagnosis, prevention, treatment conditions. We delved into dual dynamics inducing acquiring viruses, examining unique features each case. For virus-induced epilepsy, we specify virus types, elucidate mechanisms induction, emphasize neuroinflammation’s impact, analyze its effects on pharmacokinetics. detail acquired virus, interaction with existing neuroinflammation effects, changes Understanding this interplay advances precision therapies for during infections, providing mechanistic insights, identifying biomarkers therapeutic targets, supporting optimized dosing regimens. However, further studies are crucial validate tools, discover new evaluate targeted therapy safety efficacy diverse infection scenarios.

Language: Английский

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Parechovirus infection in human brain organoids: host innate inflammatory response and not neuro-infectivity correlates to neurologic disease

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 21, 2024

Picornaviruses are a leading cause of central nervous system (CNS) infections. While genotypes such as parechovirus A3 (PeV-A3) and echovirus 11 (E11) can elicit severe neurological disease, the highly prevalent PeV-A1 is not associated with CNS disease. Here, we expand our current understanding these differences in PeV-A disease using human brain organoids clinical isolates two genotypes. Our data indicate that specific due to infectivity cells both viruses productively infect similar cell tropism. Proteomic analysis shows infection significantly alters host metabolism. The inflammatory response following PeV-A3 (and E11 infection) more potent than upon infection. Collectively, findings align observations suggest role for neuroinflammation, rather viral replication, E11)

Language: Английский

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Critical role of Oas1g and STAT1 pathways in neuroinflammation: insights for Alzheimer’s disease therapeutics

Journal of Translational Medicine, Journal Year: 2025, Volume and Issue: 23(1)

Published: Feb. 14, 2025

Alzheimer's disease (AD) has a significant impact on an individual's health and places heavy burden society. Studies have emphasized the importance of microglia in progression development AD. Interferon responses Interferon-stimulated genes (ISGs) significantly function neuroinflammatory neurodegenerative diseases involving Therefore, further exploration relationship among microglia, ISGs, neuroinflammation AD is warranted. Microglia datasets from GEO database were retrieved, along with additional RNA-seq data laboratory mice. Weighted Correlation Network Analysis was used training dataset to identify gene co-expression networks. Genes black module intersected interferon-stimulated genes, differentially expressed (DEGs) identified. Machine learning algorithms applied DEGs, selected by both methods identified as hub ROC curves evaluate their diagnostic accuracy. Gene Set Enrichment performed reveal functional pathways closely relating genes. cells transfected siRNAs targeting Oas1g STAT1. Total RNA mouse brain tissues extracted, reverse-transcribed, analyzed via qRT-PCR. Proteins extracted cells, quantified, separated SDS-PAGE, transferred PVDF membranes, probed antibodies. fixed, permeabilized, blocked, stained antibodies for STAT1, then visualized photographed. Bioinformatics machine revealed that gene, AUC 0.812. associated interferon-related pathways. Expression validated models, where it upregulated after microglial activation. Knockdown experiments suggested siOas1g attenuated effect siSTAT1, expressions STAT1 p-STAT1 elevated. could reverse indicating potentially regulates ISGs through pathway. We demonstrated ISG can downregulate activation IFN-β reducing expression neuroinflammation. might be beneficial candidate prevention treatment

Language: Английский

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IRF3 regulates neuroinflammatory responses and the expression of genes associated with Alzheimer’s disease

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: Aug. 30, 2024

The pathological role of interferon signaling is emerging in neuroinflammatory disorders, yet, the specific Interferon Regulatory Factor 3 (IRF3) neuroinflammation remains poorly understood. Here, we show that global IRF3 deficiency delays TLR4-mediated microglia and attenuates hallmark features LPS-induced inflammation such as cytokine release, microglial reactivity, astrocyte activation, myeloid cell infiltration, inflammasome activation. Moreover, expression a constitutively active (S388D/S390D: IRF3-2D) induces transcriptional program reminiscent Activated Response Microglia genes associated with Alzheimer's disease, notably apolipoprotein-e. Using bulk-RNAseq IRF3-2D brain cells, identified Z-DNA binding protein-1 (ZBP1) target relevant across various disorders. Lastly, phosphorylation IRF3-dependent ZBP1 induction response to Aβ primary cultures. Together, our results identify an important regulator LPS -mediated responses highlight central disease-specific gene activation different diseases.

Language: Английский

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Genes, inflammatory response, tolerance, and resistance to virus infections in migratory birds, bats, and rodents

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Aug. 29, 2023

Normally, the host immunological response to viral infection is coordinated restore homeostasis and protect individual from possible tissue damage. The two major approaches are adopted by deal with pathogen: resistance or tolerance. nature of responses often differs between species individuals same species. Resistance includes innate adaptive immune control virus replication. Disease tolerance relies on allowing coexistence infections in minimal no clinical signs, while maintaining sufficient replication for transmission. Here, we compared virome bats, rodents migratory birds molecular mechanisms underlying symptomatic asymptomatic disease progression. We also explore influence physiology environmental influences RNA expression how it impacts whole brain transcriptome seemingly healthy semipalmated sandpiper ( Calidris pusilla ) spotted Actitis macularius ). Three time points throughout year were selected understand importance longitudinal surveys characterization virome. finally revisited evidence that upstream downstream regulation inflammatory is, respectively, associated infections.

Language: Английский

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Neurological risks of COVID-19 in women: the complex immunology underpinning sex differences

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: Nov. 14, 2023

The COVID-19 pandemic has uncovered many mysteries about SARS-CoV-2, including its potential to trigger abnormal autoimmune responses. Emerging evidence suggests women may face higher risks from COVID-induced autoimmunity manifesting as persistent neurological symptoms. Elucidating the mechanisms underlying this female susceptibility is now imperative. We synthesize key insights existing studies on how infection can lead immune tolerance loss, enabling autoreactive antibodies and lymphocyte production. These lymphocytes infiltrate central nervous system. Female sex hormones like estrogen X-chromosome mediated effects likely contribute dysregulated humoral immunity cytokine profiles among women, increasing their predisposition. also disrupt delicate immunological balance of microbiome. perturbations precipitate damage neural through demyelination, neuroinflammation, neurodegeneration – consistent with observed sequelae in women. An intentional focus elucidating differences pathogenesis needed inform prognosis assessments tailored interventions for patients. From clinical monitoring evaluating emerging immunomodulatory therapies, a nuanced women-centered approach considering hormonal status immunobiology will be vital ensure equitable outcomes. Overall, deeper into apparent specificity accelerate development solutions mitigating associated harm.

Language: Английский

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