Neuroinflammation in Alzheimer disease

Nature reviews. Immunology, Год журнала: 2024, Номер unknown

Опубликована: Дек. 9, 2024

Язык: Английский

---

Neuroinflammation is associated with Alzheimer’s disease co-pathology in dementia with Lewy bodies

Acta Neuropathologica Communications, Год журнала: 2024, Номер 12(1)

Опубликована: Май 7, 2024

Neuroinflammation and Alzheimer's disease (AD) co-pathology may contribute to progression severity in dementia with Lewy bodies (DLB). This study aims clarify whether a different pattern of neuroinflammation, such as alteration microglial astroglial morphology distribution, is present DLB cases without AD co-pathology. The load (% area immunopositivity) total (Iba1) reactive microglia (CD68 HLA-DR), astrocytes (GFAP) proteinopathies alpha-synuclein (KM51/pser129), amyloid-beta (6 F/3D) p-tau (AT8) were assessed cohort mixed + (n = 35), pure 15), 16) control 11) donors limbic neocortical brain regions using immunostaining, quantitative image analysis confocal microscopy. Regional group differences estimated linear model analysis. Morphologically, amoeboid common AD, while homeostatic small soma thin processes observed cases. A higher density swollen was cases, but not or Mixed had CD68-loads the amygdala parahippocampal gyrus than did differ astrocytic loads. Pure showed Iba1-loads CA1 CA2, CA2 subiculum, CA1-4 subiculum In associated strongly (Iba1, CD68 minimally (CD68). addition, highest activity found CA4. Confocal microscopy demonstrated co-localization large neuritic classic-cored plaques conclusion, activation largely co-pathology, response not. high regions, prevalent pathology. Our provides novel insights into molecular neuropathology DLB, highlighting importance AD.

Язык: Английский

---

Exploring the role of T cells in Alzheimer's and other neurodegenerative diseases: Emerging therapeutic insights from the T Cells in the Brain symposium

Alzheimer s & Dementia, Год журнала: 2025, Номер unknown

Опубликована: Янв. 27, 2025

Abstract This proceedings article summarizes the inaugural “T Cells in Brain” symposium held at Columbia University. Experts gathered to explore role of T cells neurodegenerative diseases. Key topics included characterization antigen‐specific immune responses, cell receptor (TCR) repertoire, microbial etiology Alzheimer's disease (AD), and microglia–T crosstalk, with a focus on how affect neuroinflammation AD biomarkers like amyloid beta tau. The also examined immunotherapies for AD, including Valacyclovir Treatment Disease (VALAD) trial, two clinical trials leveraging regulatory approaches multiple sclerosis amyotrophic lateral therapy. Additionally, single‐cell RNA/TCR sequencing other provided insights into dynamics highlights key findings from outlines future research directions further understand neurodegeneration, offering innovative therapeutic Highlights Researchers discuss study brain disorders. New technologies allow high‐throughput screening cells. Microbial infections can precede several serious chronic neurological Central peripheral responses shape pathology. Immunotherapy induce neuroinflammatory

Язык: Английский

---

Interaction of genetic variants and methylation in transcript-level expression regulation in Alzheimer’s disease by multi-omics data analysis

BMC Genomics, Год журнала: 2025, Номер 26(1)

Опубликована: Фев. 20, 2025

Alzheimer's disease (AD) presents a significant public health problem and major cause of dementia. Not only genetic but epigenetic factors contribute to complex heterogeneous molecular mechanisms underlying AD risk; in particular, single nucleotide polymorphisms (SNPs) DNA methylation can lead dysregulation gene expression the brain. Each these regulators has been independently studied well progression, however, their interactive roles, particularly when they are located differently, still remains unclear. Here, we aimed explore interplay between SNPs regulating transcript levels brain through an integrative analysis whole-genome sequencing, RNA-seq, data measured from dorsolateral prefrontal cortex. We identified 179 SNP-methylation combination pairs that showed statistically interactions associated with 67 transcripts (63 unique genes), enriched functional pathways, including immune-related post-synaptic assembly pathways. Particularly, number HLA family genes (HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DRB5, HLA-DPA1, HLA-K, HLA-DQB1, HLA-DMA) were observed as having changes interplay. Our findings especially implicate pathways targets regulatory interactions. may thus complexity pathogenies patients. study provides new knowledge context regulations, it concerns status AD.

Язык: Английский

---

Early detection of Parkinson’s disease through multiplex blood and urine biomarkers prior to clinical diagnosis

npj Parkinson s Disease, Год журнала: 2025, Номер 11(1)

Опубликована: Фев. 25, 2025

Blood and urine biomarkers are commonly used to diagnose monitor chronic diseases. We initially screened 67 biomarkers, including 4 63 blood identified 13 significantly associated with Parkinson's disease (PD). Among these, we discovered three novel markers demonstrating strong associations: phosphate (P = 1.81 × 10−3), AST/ALT ratio 8.53 10−6), immature reticulocyte fraction (IRF) 3.49 10−20). also substantiated eight well-studied elucidated the roles of two previously ambiguous biomarkers. Our analyses confirmed IGF-1 7.46 10−29) as a risk factor, C-reactive protein (CRP) 1.43 10−3) protective against PD. Genetic analysis highlighted that IRF, CRP, share significant genetic loci PD, notably at MAPT, SETD1A, HLA-DRB1, HLA-DQA1. Furthermore, Mendelian randomization (MR) suggested potential causal associations between IGF-1, several may be developing providing valuable insights for further exploration PD-related

Язык: Английский

---

Identification of key genes and signaling pathway in the pathogenesis of Huntington's disease via bioinformatics and next generation sequencing data analysis

Egyptian Journal of Medical Human Genetics, Год журнала: 2025, Номер 26(1)

Опубликована: Март 4, 2025

Abstract Background Huntington's disease (HD) could cause progressive motor deficits, psychiatric symptoms, and cognitive impairment. With the increasing use of pharmacotherapies theoretically target neurotransmitters, incidence HD is still not decreasing. However, molecular pathogenesis have been illuminate. It momentous to further examine HD. Methods The next generation sequencing dataset GSE105041 was downloaded from Gene Expression Omnibus (GEO) database. Using DESeq2 in R bioconductor package screen differentially expressed genes (DEGs) between samples normal control samples. ontology (GO) term REACTOME pathway enrichment were performed on DEGs. Meanwhile, using Integrated Interactions Database (IID) database Cytoscape software construct protein–protein interaction (PPI) network module analysis, identify hub with highest value node degree, betweenness, stress closeness scores. miRNA-hub gene regulatory TF-hub constructed analyzed. Receiver operating characteristic curves analysis for diagnostic genes. Results We identified 958 DEGs, consisting 479 up regulated DEGs down GO terms analyses by g:Profiler online results revealed that mainly enriched multicellular organismal process, developmental signaling GPCR MHC class II antigen presentation. Network Analyzer plugin PPI network, LRRK2, MTUS2, HOXA1, IL7R, ERBB3, EGFR, TEX101, WDR76, NEDD4L COMT selected as Hsa-mir-1292-5p, hsa-mir-4521, ESRRB SREBF1 are potential biomarkers predicted be associated Conclusion This study investigated key pathways interactions its complications, which might help reveal correlation complications. current investigation captured prediction, follow-up biological experiments enforced validation.

Язык: Английский

---

Investigation of the HLA locus in autopsy-confirmed progressive supranuclear palsy

Immunobiology, Год журнала: 2025, Номер unknown, С. 152892 - 152892

Опубликована: Март 1, 2025

Progressive supranuclear palsy (PSP) is a neurodegenerative disease showing pathological tau accumulation in subcortical neurons and glial cells. The human leukocyte antigen (HLA) locus on chromosome 6 polymorphic region with complex linkage patterns that has been implicated several autoimmune neurological disorders. HLA not systematically examined PSP. It unclear whether can interact to induce an mechanism. We evaluated autopsy confirmed PSP cohort (n = 44) compared allele/haplotype frequencies those of the reference group local deceased Canadian donor pool. performed HLA-Tau peptide binding prediction modelling Class II - Tau Peptide interactions. Odds ratio was 2.94 (95 % CI 1.01 8.55; p 0.047) for DQB1*06:01 allele, 2.59 1.39 4.83; 0.0025) narcolepsy-associated haplotype (DRB1*15:01-DQB1*06:02). One patient 4-repeat PSP-type pathology carrier IgLON5-associated (DRB1*10:01-DQB1*05:01). interactions revealed strong-binding peptides but PSP-protofilament fold alleles DQA1*01:02-DQB1*06:02 DQA1*01:03-DQB1*06:01. Our study suggests epitopes within may bind are found subset patients supporting notion pathophysiological component. These findings have implications subtyping stratifying therapies, including targeting immune modulation.

Язык: Английский

---

Human leukocyte antigen (HLA) Class I and II genetic relationships with brain imaging measures: a systematic review and meta-analysis

Brain Behavior and Immunity, Год журнала: 2025, Номер 128, С. 336 - 351

Опубликована: Апрель 11, 2025

Язык: Английский

---

Macrophages and HLA-Class II Alleles in Multiple Sclerosis: Insights in Therapeutic Dynamics

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(13), С. 7354 - 7354

Опубликована: Июль 4, 2024

Antigen presentation is a crucial mechanism that drives the T cell-mediated immune response and development of Multiple Sclerosis (MS). Genetic alterations within highly variable Major Histocompatibility Complex Class II (MHC II) have been proven to result in significant changes molecular basis antigen clinical course patients with both Adult-Onset MS (AOMS) Pediatric-Onset (POMS). Among numerous polymorphisms Human Leucocyte Antigens (HLA), MHC complex, HLA-DRB1*15:01 has labeled, Caucasian ethnic groups, as high-risk allele for due ability its structure increase affinity Myelin Basic Protein (MBP) epitopes. This characteristic, among others, context trimolecular complex or immunological synapsis, provides foundation autoimmunity triggered by environmental endogenous factors. As all professional presenting cells, macrophages are characterized expression often implicated formation lesions. Increased presence M1 associated progression onset disease, each involving separate but similar mechanisms. In this critical narrative review, we focus on macrophages, discussing how HLA genetic can promote dysregulation population's homeostasis periphery Central Nervous System (CNS). We also explore potential interconnection observed pathological macrophage mechanisms function diverse alleles neurodegenerative CNS, seen MS, comparing available data through prism HLA-immunogenetics. Finally, discuss experimental pharmacological approaches targeting based cell phenotype modulation genotype involvement try reveal fertile ground novel drugs.

Язык: Английский

---

Exome sequencing in Asian populations identifies low-frequency and rare coding variation influencing Parkinson’s disease risk

Nature Aging, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 21, 2024

Parkinson's disease (PD) is an incurable, progressive and common movement disorder that increasing in incidence globally because of population aging. We hypothesized the landscape rare, protein-altering variants could provide further insights into pathogenesis. Here we performed whole-exome sequencing followed by gene-based tests on 4,298 PD cases 5,512 controls Asian ancestry. showed GBA1 SMPD1 were significantly associated with risk, replication a 5,585 5,642 controls. refined variant classification using vitro assays reduced enzymatic activity display strongest association (<44% activity, odds ratio (OR) = 2.24, P 1.25 × 10−15) risk. Moreover, 80.5% carriers harbored Asian-specific p.Pro332Arg (OR 2.16; 4.47 10−8). Our findings highlight utility performing exome diverse ancestry groups to identify rare genes previously unassociated disease. Using assays, Chew, Liu, Li, Chung et al. identified protein-coding associate risk across cohorts descent.

Язык: Английский

---