Unraveling the mechanisms of NK cell dysfunction in aging and Alzheimer’s disease: insights from GWAS and single-cell transcriptomics

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Фев. 23, 2024

Background Aging is an important factor in the development of Alzheimer’s disease (AD). The senescent cells can be recognized and removed by NK cells. However, cell function gradually inactivated with age. Therefore, this study used senescence as entry point to investigate how affect AD. Methods validated correlation between cognition aging through a prospective cohort National Health Nutrition Examination Survey database. A cellular trajectory analysis population was performed using single-cell nuclear transcriptome sequencing data from patients AD different ages. genome-wide association (GWAS) outcome event, expression quantitative trait locus instrumental variable. Causal associations genes were analyzed bidirectional Mendelian randomization (MR) co-localization. Finally, clinical cohorts constructed validate key genes. Results demonstrated 2,171 older adults over 60 years Gene regulation revealed that most highly active transcription factors concentrated subpopulation trajectories for age populations. MR co-localization analyses CHD6 may one influencing Conclusion We explored levels cohorts, data, GWAS found there some correlations It also provides basis potential causation.

Язык: Английский

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The Genomic Intersection of Oligodendrocyte Dynamics in Schizophrenia and Aging Unravels Novel Pathological Mechanisms and Therapeutic Potentials

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(8), С. 4452 - 4452

Опубликована: Апрель 18, 2024

Schizophrenia is a significant worldwide health concern, affecting over 20 million individuals and contributing to potential reduction in life expectancy by up 14.5 years. Despite its profound impact, the precise pathological mechanisms underlying schizophrenia continue remain enigmatic, with previous research yielding diverse occasionally conflicting findings. Nonetheless, one consistently observed phenomenon brain imaging studies of patients disruption white matter, bundles myelinated axons that provide connectivity rapid signalling between regions. Myelin produced specialised glial cells known as oligodendrocytes, which have been shown be disrupted post-mortem analyses patients. Oligodendrocytes are generated throughout major population oligodendrocyte progenitor (OPC), essential for matter plasticity. Notably, decline specific subpopulation OPC has identified principal factor loss aging brain, suggesting this may also schizophrenia. In review, we analysed genomic databases pinpoint intersections identify shared cognitive dysfunction.

Язык: Английский

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Characterization of RNA cargo from extracellular vesicles obtained from cerebrospinal fluid and plasma samples in schizophrenia participants and healthy volunteers

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 4, 2025

Abstract Biomarkers that are clinically useful for the diagnosis and treatment of schizophrenia lacking. critical tools reduce incidence misdiagnosis, identify subgroups patients, assist in proper characterization patient phenotypes, predict response to or development side effects, can serve as targets novel therapeutic interventions. In this study, we evaluated small (< 200 nucleotide) long (> RNAs found extracellular vesicles (EVs) isolated from cerebrospinal fluid (CSF) plasma individuals with spectrum disorders (SSD) healthy volunteers (HV). As EVs carry cargo all tissues body, they act a potential proxy tissue origin, including cells brain. We compared transcriptomic features these two biofluids examined their ability discriminate between SSD HV participants, identifying total 141 differentially expressed genes, some which have been previously associated SSD. Next, cell-types give rise SSD-associated CSF RNA cargo, majority were predominantly excitatory neurons. Our results highlight both source relevant biomarkers, molecular insight into disease mechanisms.

Язык: Английский

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Decoding microglial functions in Alzheimer’s disease: insights from human models

Trends in Immunology, Год журнала: 2025, Номер unknown

Опубликована: Март 1, 2025

Язык: Английский

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Integrative multi-omics QTL colocalization maps regulatory architecture in aging human brain

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Апрель 20, 2025

Abstract Multi-trait QTL (xQTL) colocalization has shown great promises in identifying causal variants with shared genetic etiology across multiple molecular modalities, contexts, and complex diseases. However, the lack of scalable efficient methods to integrate large-scale multi-omics data limits deeper insights into xQTL regulation. Here, we propose ColocBoost , a multi-task learning method that can scale hundreds traits, while accounting for within genomic region interest. employs specialized gradient boosting framework adaptively couple colocalized traits performing variant selection, thereby enhancing detection weaker signals compared existing pairwise multi-trait methods. We applied genome-wide 17 gene-level single-nucleus bulk from aging brain cortex ROSMAP individuals (average N = 595), encompassing 6 cell types, 3 regions modalities (expression, splicing, protein abundance). Across xQTLs, identified 16,503 distinct events, exhibiting 10.7(±0.74)-fold enrichment heritability 57 diseases/traits showing strong concordance element-gene pairs validated by CRISPR screening assays. When against Alzheimer’s disease (AD) GWAS, up 2.5-fold more loci, explaining twice AD fine-mapping without integration. This improvement is largely attributable ’s enhanced sensitivity detecting gene-distal colocalizations, as supported known enhancer-gene links, highlighting its ability identify biologically plausible susceptibility loci underlying regulatory mechanisms. Notably, several genes including BLNK CTSH showed sub-threshold associations but were through colocalizations which provide new functional support their involvement pathogenesis.

Язык: Английский

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Cell type-specific associations with Alzheimer’s Disease conserved across racial and ethnic groups

Опубликована: Апрель 15, 2025

Abstract Genomic studies at single-cell resolution have implicated multiple cell types associated with clinical and pathological traits in Alzheimer’s Disease (AD), but not examined common features across broad, multi-ethnic populations, regions. To bridge this gap, we performed single-nucleus RNA-seq ATAC-seq profiling of cortical subcortical brain regions from post-mortem samples Non-Latin White, African American, Latin donors (the latter any race). Using discrete continuous dissection molecular programs, elucidate cell-type-specific glial neuronal signatures AD population groups. Notably, found that microglial ( GPNMB +, CD74 CR1 + subgroups) astrocyte SERPINH1 WIF1 are worse phenotypes all three We also report gene expression factors oligodendrocytes captured by clusters, yet still show strong associations disease phenotypes. Finally, observe these cellular identities programs separate cognitively impaired into 6 molecularly distinct subgroups span racial ethnic Overall, our study identifies key shared groups, provides an initial data set underscores how representative sampling can capture conserved as well heterogeneity, leading to better prioritization for further investigation.

Язык: Английский

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Alzheimer’s Disease, Obesity, and Type 2 Diabetes: Focus on Common Neuroglial Dysfunctions (Critical Review and New Data on Human Brain and Models)

Brain Sciences, Год журнала: 2024, Номер 14(11), С. 1101 - 1101

Опубликована: Окт. 30, 2024

Obesity, type 2 diabetes (T2D), and Alzheimer's disease (AD) are pathologies that affect millions of people worldwide. They have no effective therapy difficult to prevent control when they develop. It has been known for many years these diseases pathogenic aspects in common. We highlight this review neuroglial cells (astroglia, oligodendroglia, microglia) play a vital role the origin, clinical-pathological development, course brain neurodegeneration. Moreover, we include new results T2D-AD mouse model (APP+PS1 mice on high-calorie diet) investigating.

Язык: Английский

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Transcriptional Regulation of human NMNAT2: Insights from 3D Genome Sequencing and Bioinformatics

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 8, 2024

Abstract Nicotinamide mononucleotide adenylyl transferases 2 (NMNAT2) is a crucial nicotinamide adenine dinucleotide (NAD)-synthesizing enzyme essential for neuronal health. In the Religious Orders Study/Memory and Aging Project (ROSMAP), human brain levels of NMNAT2 mRNA positively correlated with cognitive capabilities in older adults. abundance significantly reduced following various insults or proteinopathies. To elucidate transcriptional regulation NMNAT2, we employed circular chromosome conformation capture followed by high-throughput sequencing (4C-seq) to identify potential enhancer silencer regions determining genomic interacting promoter SH-SY5Y cells. We discovered distinct interactomes undifferentiated versus neuron-like Utilizing bioinformatics analyses, identified putative factors NMNAT2-associated genes. Notably, many these genes showed significant correlation ∼400 single-nuclei RNA-seq datasets from ROSMAP. Additionally, using CRISPR-Cas9 strategies, confirmed requirement two specific within four transcription regulating transcription. summary, our study identifies loci containing regulatory elements predicts associated through computational analyses.

Язык: Английский

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Exploring and Validating Key Genetic Biomarkers for Diagnosis of Parkinson's Disease

Brain Research Bulletin, Год журнала: 2024, Номер unknown, С. 111165 - 111165

Опубликована: Дек. 1, 2024

Parkinson's disease (PD) is a neurological condition characterized by complex genetic basic, and the reliable diagnosis of PD remained limited.

Язык: Английский

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Alzheimer's disease‐associated CD83(+) microglia are linked with increased immunoglobulin G4 and human cytomegalovirus in the gut, vagal nerve, and brain

Alzheimer s & Dementia, Год журнала: 2024, Номер unknown

Опубликована: Дек. 19, 2024

Abstract INTRODUCTION While there may be microbial contributions to Alzheimer's disease (AD), findings have been inconclusive. We recently reported an AD‐associated CD83(+) microglia subtype associated with increased immunoglobulin G4 (IgG4) in the transverse colon (TC). METHODS used immunohistochemistry (IHC), IgG4 repertoire profiling, and brain organoid experiments explore this association. RESULTS superior frontal gyrus (SFG) are elevated human cytomegalovirus (HCMV) TC, anti‐HCMV cerebrospinal fluid, both HCMV SFG vagal nerve. This association was replicated independent AD cohort. HCMV‐infected cerebral organoids showed accelerated pathophysiological features (Aβ42 pTau‐212) neuronal death. DISCUSSION Findings indicate complex, cross‐tissue interactions between adaptive immune response persons AD. opportunity for antiviral therapy biomarker evidence of HCMV, IgG4, or microglia. Highlights Cross‐tissue interaction a subset Presence microglial gut. also presence cortex Replication key cohort subjects. infection accelerates production neuropathological features.

Язык: Английский

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