The neuroimmune nexus: unraveling the role of the mtDNA-cGAS-STING signal pathway in Alzheimer’s disease

Molecular Neurodegeneration, Год журнала: 2025, Номер 20(1)

Опубликована: Март 4, 2025

The relationship between Alzheimer's disease (AD) and neuroimmunity has gradually begun to be unveiled. Emerging evidence indicates that cyclic GMP-AMP synthase (cGAS) acts as a cytosolic DNA sensor, recognizing damage-associated molecular patterns (DAMPs), inducing the innate immune response by activating stimulator of interferon genes (STING). Dysregulation this pathway culminates in AD-related neuroinflammation neurodegeneration. A substantial body mitochondria are involved critical pathogenic mechanisms AD, whose damage leads release mitochondrial (mtDNA) into extramitochondrial space. This leaked mtDNA serves DAMP, various pattern recognition receptors defense networks brain, including cGAS-STING pathway, ultimately leading an imbalance homeostasis. Therefore, modulation mtDNA-cGAS-STING restore neuroimmune homeostasis may offer promising prospects for improving AD treatment outcomes. In review, we focus on during stress activation pathway. Additionally, delve research progress further discuss primary directions potential hurdles developing targeted therapeutic drugs, gain deeper understanding pathogenesis provide new approaches its therapy.

Язык: Английский

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The type‐I interferon response potentiates seeded tau aggregation and exacerbates tau pathology

Alzheimer s & Dementia, Год журнала: 2023, Номер 20(2), С. 1013 - 1025

Опубликована: Окт. 17, 2023

Abstract INTRODUCTION Signatures of a type‐I interferon (IFN‐I) response are observed in the post mortem brain Alzheimer's disease (AD) and other tauopathies. However, effect IFN‐I on pathological tau accumulation remains unclear. METHODS We examined effects signaling primary neural culture models seeded aggregation P301S‐tau transgenic mouse context genetic deletion receptor (IFNAR). RESULTS Polyinosinic:polycytidylic acid (PolyI:C), synthetic analog viral nucleic acids, evoked potent cytokine that enhanced an IFN‐I‐dependent manner. IFN‐I‐induced vulnerability could be pharmacologically prevented was intrinsic to neurons. Aged mice lacking Ifnar1 had significantly reduced pathology compared with intact IFN signaling. DISCUSSION identify critical role for potentiating aggregation. is therefore identified as potential therapeutic target AD Highlights Type‐I promotes cultures. IFNAR inhibition prevents driven sensitivity Tau aged IFNAR.

Язык: Английский

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Sex-specific biphasic alpha-synuclein response and alterations of interneurons in a COVID-19 hamster model

EBioMedicine, Год журнала: 2024, Номер 105, С. 105191 - 105191

Опубликована: Июнь 13, 2024

Coronavirus disease 2019 (COVID-19) frequently leads to neurological complications after recovery from acute infection, with higher prevalence in women. However, mechanisms by which SARS-CoV-2 disrupts brain function remain unclear and treatment strategies are lacking. We previously demonstrated neuroinflammation the olfactory bulb of intranasally infected hamsters, followed alpha-synuclein tau accumulation cortex, thus mirroring pathogenesis neurodegenerative diseases such as Parkinson's or Alzheimer's disease.

Язык: Английский

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Gut Microbiota as a Modifier of Huntington’s Disease Pathogenesis

Journal of Huntington s Disease, Год журнала: 2024, Номер 13(2), С. 133 - 147

Опубликована: Май 10, 2024

Huntingtin (HTT) protein is expressed in most cell lineages, and the toxicity of mutant HTT multiple organs may contribute to neurological psychiatric symptoms observed Huntington's disease (HD). The proteostasis neurotoxicity are influenced by intracellular milieu responses environmental signals. Recent research has highlighted a prominent role gut microbiota brain immune system development, aging, progression disorders. Several studies suggest that might disrupt homeostasis (known as dysbiosis) impact pathogenesis HD. Dysbiosis been HD patients, animal models it coincides with aggregation, abnormal behaviors, reduced lifespan. This review article aims highlight potential pathways within microbiota-gut-immune-central nervous (CNS) axis. Understanding functions Wild-Type (WT) these associated networks elucidate novel pathogenic pathways, identify biomarkers peripheral therapeutic targets for

Язык: Английский

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Amyloid precursor protein induces reactive astrogliosis

Acta Physiologica, Год журнала: 2024, Номер 240(6)

Опубликована: Апрель 8, 2024

Abstract Aim Astrocytes respond to stressors by acquiring a reactive state characterized changes in their morphology and function. Molecules underlying astrogliosis, however, remain largely unknown. Given that several studies observed increase the Amyloid Precursor Protein (APP) astrocytes, we here test whether APP plays role astrogliosis. Methods We investigated instigates astroglios examining vitro vivo function of naive APP‐deficient astrocytes response well‐established stressors. Results Overexpression cultured led remodeling intermediate filament network, enhancement cytokine production, activation cellular programs centered around interferon (IFN) pathway, all signs Conversely, deletion abrogated network blunted expression IFN‐stimulated gene products lipopolysaccharide. Following traumatic brain injury (TBI), mouse also exhibited an association between IFN, while curbed glial fibrillary acidic protein canonically TBI. Conclusions The thus represents candidate molecular inducer regulator This finding has implications for understanding pathophysiology neurodegenerative other diseases nervous system astrogliosis opens potential new therapeutic avenues targeting its pathways modulate

Язык: Английский

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In sickness and in health—Type I interferon and the brain

Frontiers in Aging Neuroscience, Год журнала: 2024, Номер 16

Опубликована: Май 7, 2024

Type I interferons (IFN-I) represent a group of pleiotropic cytokines renowned for their antiviral activity and immune regulatory functions. A multitude studies have unveiled critical role IFN-I in the brain, influencing various neurological processes diseases. In this mini-review, highlight recent findings on IFN-I's effects brain aging, Alzheimer's disease (AD) progression, central nervous system (CNS) homeostasis. The multifaceted influence health sheds light complex interplay between responses processes. Of particular interest is cGAS-STING-IFN-I axis, which extensively participates aging forms neurodegeneration. Understanding intricate its associated pathways CNS not only advances our comprehension but also presents opportunities developing interventions to modify process neurodegeneration prevent age-related cognitive decline.

Язык: Английский

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A parasite odyssey: An RNA virus concealed in Toxoplasma gondii

Virus Evolution, Год журнала: 2024, Номер 10(1)

Опубликована: Янв. 1, 2024

We are entering a 'Platinum Age of Virus Discovery', an era marked by exponential growth in the discovery virus biodiversity, and driven advances metagenomics computational analysis. In ecosystem human (or any animal) there more species viruses than simply those directly infecting animal cells. Viruses can infect all organisms constituting microbiome, including bacteria, fungi, unicellular parasites. Thus complexity possible interactions between host, microbe, is unfathomable. To understand this interaction network we must employ computationally assisted virology as means analyzing interpreting millions available samples to make inferences about ways which may intersect health. From viral screen neuronal datasets, identified novel narnavirus Apocryptovirus odysseus (Ao) likely infects neurotropic parasite Toxoplasma gondii. Previously, several parasitic protozoan (PPVs) have been mechanistically established triggers host innate responses, here present silico evidence that Ao plausible pro-inflammatory factor mouse cells infected T. gondii billions people worldwide, yet prognosis toxoplasmosis disease highly variable, PPVs like could function hitherto undescribed hypervirulence factor. broader over 7.6 million samples, explored phylogenetically proximal discovered nineteen species, found libraries annotated vertebrate transcriptome or metatranscriptomes. While containing genus narnaviruses derived from sheep, goat, bat, rabbit, chicken, pigeon presence strongly predictive Apicomplexa nucleic acid co-occurrence, supporting fact parasite-infecting viruses. This proof-of-concept study rapidly analyze datasets distilled mechanistically, ecologically, refined hypothesis. predict diverged RNA biologically infection, Ao, other it, will modulate afflicts worldwide.

Язык: Английский

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Type I interferon signaling, cognition and neurodegeneration following COVID-19: update on a mechanistic pathogenetic model with implications for Alzheimer’s disease

Frontiers in Human Neuroscience, Год журнала: 2024, Номер 18

Опубликована: Март 18, 2024

COVID-19’s effects on the human brain reveal a multifactorial impact cognition and potential to inflict lasting neuronal damage. Type I interferon signaling, pathway that represents our defense against pathogens, is primarily affected by COVID-19. however, known mediate cognitive dysfunction upon its dysregulation following synaptopathy, microgliosis In previous studies, we proposed model of outside-in tonic IFN-I signaling in This disruption would be mediated crosstalk between central peripheral immunity, could potentially establish feed-forward leading neuroinflammation potentially, neurodegeneration. We for CNS, second-order mediators intrinsic disease-associated molecular patterns (DAMPs) such as proteopathic seeds, without requirement neuroinvasion sustain inflammation. Selective vulnerability neurogenesis sites then lead clinical manifestations anosmia impairment. Since inception at beginning pandemic, growing body studies has provided further evidence SARS-CoV-2 infection CNS cognition. Several preclinical have displayed tauopathy gene expression neuropathological data new cases, correspondingly. Furthermore, neurodegeneration identified with predilection extended olfactory network furthermore supports neuroanatomical concept model, independence from fulminant encephalitis cause this perspective, summarize plausible mechanism impairment setting, contribution Alzheimer’s disease interplay

Язык: Английский

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Cell redistribution of G quadruplex‐structured DNA is associated with morphological changes of nuclei and nucleoli in neurons during tau pathology progression

Brain Pathology, Год журнала: 2024, Номер unknown

Опубликована: Апрель 22, 2024

Abstract While the double helical structure has long been its iconic representation, DNA is structurally dynamic and can adopt alternative secondary configurations. Specifically, guanine‐rich sequences fold in guanine quadruplexes (G4) structures. These G4 play pivotal roles as regulators of gene expression genomic stability, influence protein homeostasis. Despite their significance, association with neurodegenerative diseases such Alzheimer's disease (AD) underappreciated. Recent findings have identified predicted to form sarkosyl‐insoluble aggregates from AD brains, questioning involvement G4‐structured (G4 DNA) pathology. Using immunofluorescence coupled confocal microscopy analysis we investigated impact tau pathology, a hallmark tauopathies including AD, on distribution murine neurons relevance brains. In healthy neurons, detected nuclei notable presence nucleoli. However, transgenic mouse model pathology (THY‐Tau22), early stages exhibit an impairment nuclear DNA. addition, accumulates cytoplasm exhibiting oligomerized oxidative damage. This altered persists later stage when larger are present. Still cytoplasmic deposition does not appear be critical factor aggregation process. Similar patterns observed cortex. Furthermore, disturbance associated various changes size neuronal nucleoli, indicative responses stress activation pro‐survival mechanisms. Our results shed light significant dynamics nucleolar mechanobiology neurons. reveal new dimensions etiopathogenesis tauopathies.

Язык: Английский

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SARS-CoV-2-Induced Type I Interferon Signaling Dysregulation in Olfactory Networks Implications for Alzheimer’s Disease

Current Issues in Molecular Biology, Год журнала: 2024, Номер 46(5), С. 4565 - 4579

Опубликована: Май 10, 2024

Type I interferon signaling (IFN-I) perturbations are major drivers of COVID-19. Dysregulated IFN-I in the brain, however, has been linked to both reduced cognitive resilience and neurodegenerative diseases such as Alzheimer’s. Previous works from our group have proposed a model where peripheral induction may be relayed CNS, even absence fulminant infection. The aim study was identify significantly enriched signatures genes along transolfactory route, utilizing published datasets nasal mucosa olfactory bulb amygdala transcriptomes COVID-19 patients. We furthermore sought these signature gene networks associated with Alzheimer’s disease pathology risk. Gene expression data involving epithelium, bulb, patients transcriptomic were scrutinized for pathways. set enrichment analyses gene–Venn approaches used determine signatures. Agora web resource risk based on its aggregated multi-omic data. For all analyses, false discovery rates (FDR) <0.05 considered statistically significant. Pathways type found samples tested. Each by IFITM OAS family genes. A 14-gene CNS response pathology, whereas nine increased Agora. Our provides further support dysregulation extended network reconstructed herein, ranging epithelium extending amygdala. 14 implicated this dysregulated pathway among which HLA-C, HLA-B, HLA-A, PSMB8, IFITM3, HLA-E, IFITM1, OAS2, MX1 conferring latter. Further research into druggability IFNb therapeutics warranted.

Язык: Английский

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