Changes in the Public IgM Repertoire and its Idiotypic Connectivity in Alzheimer's Disease and Frontotemporal Dementia DOI Creative Commons
Shina Pashova,

Peter Petrov,

Sena Karachanak-Yankova

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 17, 2024

Abstract Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are prevalent neurodegenerative disorders. Early diagnosis is challenging due to the lack of definitive biomarkers reliance on invasive procedures. Immune biomarkers, particularly those reflecting interaction between central nervous system (CNS) peripheral immune system, have shown promise for non-invasive detection through blood samples. This study investigates reactivity serum IgM IgG from AD FTD patients against a library mimotopes representing public reactivities in healthy donors. Serum samples AD, FTD, other dementias (ND), controls were tested peptide microarrays. The pooled mitigate individual variability. data analyzed using graphs represent cross-reactivity networks. analysis revealed distinct patterns studied groups. Public showed significant correlations with conditions, exhibiting loss or gain specific reactivities. Graph highlighted differences graph density, clustering, assortativity parameters control Idiotypic reactivities, IgM, more connected compared diseases. Furthermore, clusters distinctions providing additional differentiation. A number self proteins related neurodegeneration proved sequences homologous associated mimotopes. Thus, repertoire, characterized by its broad inherent autoreactivity, offers valuable insights into immunological alterations supports potential profiles as another compartment early differentiation FTD.

Language: Английский

Tracking neuroinflammatory biomarkers in Alzheimer’s disease: a strategy for individualized therapeutic approaches? DOI Creative Commons
Simone Lista, Bruno P. Imbimbo,

Margherita Grasso

et al.

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

Published: July 30, 2024

Abstract Background Recent trials of anti-amyloid-β (Aβ) monoclonal antibodies, including lecanemab and donanemab, in early Alzheimer disease (AD) showed that these drugs have limited clinical benefits their use comes with a significant risk serious adverse events. Thus, it seems crucial to explore complementary therapeutic approaches. Genome-wide association studies identified robust associations between AD several genes related immune response, but not restricted CD33 TREM2 . Here, we critically reviewed the current knowledge on candidate neuroinflammatory biomarkers role characterizing pathophysiology AD. Main body Neuroinflammation is recognized be contributing component pathogenesis. The fact neuroinflammation most likely present from earliest pre-stages co-occurs deposition Aβ reinforces need precisely define sequence nature Numerous involving anti-inflammatory previously yielded unfavorable outcomes mild-to-moderate Although reasons behind failures remain unclear, may include time target selected for intervention. Indeed, our review, observed stage-dependent process brain. While initial activation glial cells counteracts brain deposition, downregulation functional state microglia occurs at more advanced stages. To address this issue, personalized modulation therapy required. emergence reliable blood-based biomarkers, particularly fibrillary acidic protein, marker reactive astrocytes, facilitate classification patients based ATI(N) biomarker framework. This expands upon traditional (“A”), tau (“T”), neurodegeneration (“N”), by incorporating novel inflammatory (“I”). Conclusions review outlines potential and, importantly, emphasizes longitudinal analyses, which are needed accurately monitor dynamics cerebral inflammation. Such precise information place will required before interventions can considered evaluation. We propose an effective anti-neuroinflammatory should specifically while considering individual status patients.

Language: Английский

Citations

16
Fluid-based biomarkers for neurodegenerative diseases DOI Creative Commons
Yongliang Cao, Yifei Xu, Meiqun Cao

et al.

Ageing Research Reviews, Journal Year: 2025, Volume and Issue: unknown, P. 102739 - 102739

Published: March 1, 2025

Language: Английский

Citations

1
APOE ε4–associated downregulation of the IL‐7/IL‐7R pathway in effector memory T cells: Implications for Alzheimer's disease DOI Creative Commons
Yingjie Zhang, Cheng Yan, Hailiang Tang

et al.

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(9), P. 6441 - 6455

Published: Aug. 11, 2024

Abstract INTRODUCTION The apolipoprotein E ( APOE ) ε4 allele exerts a significant influence on peripheral inflammation and neuroinflammation, yet the underlying mechanisms remain elusive. METHODS present study enrolled 54 patients diagnosed with late‐onset Alzheimer's disease (AD; including 28 carriers 26 non‐carriers). Plasma inflammatory cytokine concentration was assessed, alongside bulk RNA sequencing (RNA‐seq) single‐cell (scRNA‐seq) analysis of blood mononuclear cells (PBMCs). RESULTS tumor necrosis factor α, interferon γ, interleukin (IL)‐33 levels increased in but IL‐7 expression notably decreased. A negative correlation observed between plasma level hippocampal atrophy degree. Additionally, IL‐7R CD28 also decreased PBMCs carriers. ScRNA‐seq data results indicated that changes were mainly related to CD4+ Tem (effector memory) CD8+ T cells. DISCUSSION These findings shed light role downregulated IL‐7/IL‐7R pathway associated modulating neuroinflammation atrophy. Highlights decreases (IL)‐7 aggravates disease. is negatively degree signaling Dysregulation signal pathways enriches

Language: Английский

Citations

6
Differential DNA methylation in blood as potential mediator of the association between ambient PM2.5 and cerebrospinal fluid biomarkers of Alzheimer's disease among a cognitively normal population-based cohort DOI
Tszshan Ma, Jiaqi Liu, Donghai Liang

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 16, 2025

Fine particulate matter (PM 2.5 ) is a known risk factor for Alzheimer's disease (AD), with emerging evidence linking PM exposure to cerebrospinal fluid (CSF) biomarkers in pre-clinical stages. However, the role of DNA methylation (DNAm) as potential mediator this relationship among cognitively normal individuals remains largely unexplored. In 535 individuals, we assessed genome-wide blood DNAm, CSF Aβ 42 concentrations, and residential year preceding collection. Multi-stage comprehensive mediation analyses were conducted. Nine CpG sites mediated -Aβ42 association, significant natural indirect effects (NIEs) eight CpGs, mediating 14-43% effect. The joint NIE all nine CpGs was -0.115 (95% CI: -0.215, -0.101) per 1 ug/m 3 increase exposure. Six are annotated genes implicated neuroinflammatory pathways. Our findings suggest that differential particularly neuroinflammation-related genes, mediates toxicity AD's stage.

Language: Английский

Citations

0
Elevated plasma neurofilament light was associated with multi-modal neuroimaging features in Alzheimer’s disease signature regions and predicted future tau deposition DOI Creative Commons
Qili Hu,

Mengqiu Shi,

Yunfei Li

et al.

BMC Neurology, Journal Year: 2024, Volume and Issue: 24(1)

Published: July 6, 2024

Abstract Background Neurofilament Light (NfL) is a biomarker for early neurodegeneration in Alzheimer’s disease (AD). This study aims to examine the association between plasma NfL and multi-modal neuroimaging features across AD spectrum whether predicts future tau deposition. Methods The present recruited 517 participants comprising Aβ negative cognitively normal (CN-) (n = 135), positive (CN +) ( n 64), individuals with amnestic mild cognitive impairment (aMCI) 212), those diagnosed dementia 106). All underwent examinations. Cross-sectional longitudinal associations neuro-imaging were evaluated using partial correlation analysis linear mixed effects models. We also used regression investigate of baseline PET load. Mediation was explore effect on cognition mediated by these imaging biomarkers. Results results showed that levels rate change associated deposition, brain atrophy, connectome, glucose metabolism, perfusion signature regions P <0.05). In both CN MCI participants, significant predictive value elevating burden left medial orbitofrontal cortex para-hippocampus (β 0.336, 0.032; β 0.313, 0.047). Lastly, performance. Conclusions supports AD-vulnerable its

Language: Английский

Citations

3
Neuronal apoE4 induces early hyperexcitability in select populations of hippocampal neurons by altering Nell2 expression DOI Open Access
Dennis R. Tabuena, Sung-Soo Jang, Brian P. Grone

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Aug. 29, 2023

ABSTRACT The full impact of apolipoprotein E4 (APOE4), the strongest genetic risk factor for Alzheimer’s disease (AD), on neuronal and network function remains unclear. We found hippocampal region-specific hyperexcitability in young APOE4 knock-in (E4-KI) mice which predicted cognitive deficits at old age. Network E4-KI was mediated by subpopulations smaller hyperexcitable neurons that were eliminated selective removal APOE4. Aged exhibited granule cells, a progressive inhibitory deficit, E/I imbalance dentate gyrus, exacerbating hyperexcitability. Single-nucleus RNA-sequencing revealed cell type-specific age-dependent transcriptomic changes, including Nell2 overexpression mice. Reducing expression specific types with CRISPRi rescued their abnormal excitability phenotypes, implicating as cause APOE4-induced These findings highlight early electrophysiological alterations underlying dysfunction its contribution to AD pathogenesis aging.

Language: Английский

Citations

4
Changes in the Public IgM Repertoire and its Idiotypic Connectivity in Alzheimer's Disease and Frontotemporal Dementia DOI Creative Commons
Shina Pashova,

Peter Petrov,

Sena Karachanak-Yankova

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 17, 2024

Abstract Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are prevalent neurodegenerative disorders. Early diagnosis is challenging due to the lack of definitive biomarkers reliance on invasive procedures. Immune biomarkers, particularly those reflecting interaction between central nervous system (CNS) peripheral immune system, have shown promise for non-invasive detection through blood samples. This study investigates reactivity serum IgM IgG from AD FTD patients against a library mimotopes representing public reactivities in healthy donors. Serum samples AD, FTD, other dementias (ND), controls were tested peptide microarrays. The pooled mitigate individual variability. data analyzed using graphs represent cross-reactivity networks. analysis revealed distinct patterns studied groups. Public showed significant correlations with conditions, exhibiting loss or gain specific reactivities. Graph highlighted differences graph density, clustering, assortativity parameters control Idiotypic reactivities, IgM, more connected compared diseases. Furthermore, clusters distinctions providing additional differentiation. A number self proteins related neurodegeneration proved sequences homologous associated mimotopes. Thus, repertoire, characterized by its broad inherent autoreactivity, offers valuable insights into immunological alterations supports potential profiles as another compartment early differentiation FTD.

Language: Английский

Citations

0