Shattering the Amyloid Illusion: The Microbial Enigma of Alzheimer’s Disease Pathogenesis—From Gut Microbiota and Viruses to Brain Biofilms

Microorganisms, Journal Year: 2025, Volume and Issue: 13(1), P. 90 - 90

Published: Jan. 5, 2025

For decades, Alzheimer's Disease (AD) research has focused on the amyloid cascade hypothesis, which identifies amyloid-beta (Aβ) as primary driver of disease. However, consistent failure Aβ-targeted therapies to demonstrate efficacy, coupled with significant safety concerns, underscores need rethink our approach AD treatment. Emerging evidence points microbial infections environmental factors in pathoetiology. Although a definitive causal link remains unestablished, collective is compelling. This review explores unconventional perspectives and emerging paradigms regarding involvement pathogenesis, emphasizing gut-brain axis, brain biofilms, oral microbiome, viral infections. Transgenic mouse models show that gut microbiota dysregulation precedes Aβ accumulation, signaling pathways. Viral like Herpes Simplex Virus Type 1 (HSV-1) Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) may lead by modulating host processes immune system. peptide's antimicrobial function response infection might inadvertently promote AD. We discuss potential microbiome-based promising strategies for managing potentially preventing progression. Fecal transplantation (FMT) restores balance, reduces improves cognition preclinical models. Probiotics prebiotics reduce neuroinflammation plaques, while antiviral targeting HSV-1 vaccines shingles vaccine mitigate pathology. Developing effective treatments requires standardized methods identify measure patients, enabling personalized address individual contributions pathogenesis. Further needed clarify interactions between microbes Aβ, explore bacterial interplay, understand their broader effects translate these insights into clinical interventions.

Language: Английский

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Identification of therapeutic targets for Alzheimer’s Disease Treatment using bioinformatics and machine learning

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Jan. 31, 2025

Alzheimer's disease (AD) is a complex neurodegenerative disorder that currently lacks effective treatment options. This study aimed to identify potential therapeutic targets for the of AD using comprehensive bioinformatics methods and machine learning algorithms. By integrating differential gene expression analysis, weighted co-expression network Mfuzz clustering, single-cell RNA sequencing, algorithms including LASSO regression, SVM-RFE, random forest, five hub genes related AD, PLCB1, NDUFAB1, KRAS, ATP2A2, CALM3 were identified. in particular, exhibited highest diagnostic value showed significant correlation with Braak stages neuronal expression. Furthermore, Noscapine, PX-316, TAK-901 selected as drugs based on PLCB1. research provides reliable method discovery construction models, offering important insights directions future strategies drug development.

Language: Английский

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APOE ε4–associated downregulation of the IL‐7/IL‐7R pathway in effector memory T cells: Implications for Alzheimer's disease

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

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Single-cell and spatial analysis reveals the interaction between ITLN1+ foam cells and SPP1+ macrophages in atherosclerosis

Frontiers in Cardiovascular Medicine, Journal Year: 2025, Volume and Issue: 12

Published: Feb. 13, 2025

Introduction Cardiovascular disease (CVD) caused by atherosclerosis (AS) remains the leading cause of mortality in developed countries. Understanding cellular heterogeneity within inflammatory microenvironment is crucial for advancing management strategies. This study investigates regulatory functions distinct cell populations AS pathogenesis, focusing on interaction between vascular smooth muscle (VSMC)-derived ITLN1 + foam cells and SPP1 FABP5 macrophages. Methods We employed single-cell RNA sequencing to characterize plaques. Correlation analyses CellChat package were utilized elucidate intercellular communication networks among various types. The functional roles key subsets macrophages VSMCs assessed using Gene Ontology (GO) Kyoto Encyclopedia Genes Genomes (KEGG) pathway analyses. Pseudotime trajectory analysis was conducted explore dynamics VSMC differentiation. Additionally, spatial transcriptomics used demonstrate physical interactions different subpopulations. Results identified significant infiltration macrophage clusters AS, with being highly enriched These associated lipid transport, storage, migration pathways. A subset derived from exhibited robust expression markers metabolism-related genes. indicated that represent a terminal stage differentiation, characterized elevated genes linked synthesis progression. Spatial revealed macrophages, mediated MIF-(CD74 CD44) SPP1-CD44 ligand-receptor axes. Discussion Our findings underscore critical crosstalk promoting accumulation Targeting this cell-cell may offer new therapeutic avenues managing atherosclerosis. Further validation these mechanisms necessary develop effective immunotherapeutic strategies against AS.

Language: Английский

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Association between plasma cytokine levels and multiple neuroimaging modalities in mild cognitive impairment

Journal of Alzheimer s Disease, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 16, 2025

Background The relationship between peripheral cytokines and neuroimaging biomarkers for Alzheimer's disease (AD) is not yet well established. Objective To determine the association of cytokine plasma levels with brain amyloid deposition, cortical glucose metabolism, hippocampal volume, white matter lesions (WMLs) in older adults mild cognitive impairment (MCI). Methods We recruited 50 individuals amnestic MCI (25 men 25 women; median age, 75 years) performed analysis, 11 C-Pittsburgh compound-B positron-emission tomography (PiB-PET), 18 F-fluorodeoxyglucose tomography, magnetic resonance imaging. Global PiB fluorodeoxyglucose (FDG) uptake were assessed by ratio voxel number-weighted average mean frontal, temporoparietal, posterior cingulate, reference to cerebellum. Fazekas scale was used evaluate WMLs. Plasma 48 simultaneously measured bead-based multiplex assays. Results IL-2Ra, IL-3, IL-5, IL-7, IL-9, IL-16, IL-18, fibroblast growth factor (FGF-basic), granulocyte colony-stimulating (G-CSF), granulocyte–macrophage (GM-CSF), macrophage inflammatory protein-1α (MIP-1α), regulated on activation, normal T-cell expressed secreted (RANTES), tumor necrosis factor-α (TNF-α), cutaneous attracting chemokine (CTACK), growth-regulated oncogene α (GROα), hepatocyte (HGF), interferon-α2 (IFN-α2), leukemia inhibitory (LIF), monocyte chemoattractant protein-3 (MCP-3), β-nerve (β-NGF), stem cell (SCF), factor-β (SCGF-β), TNF-related apoptosis-inducing ligand (TRAIL) significantly associated global uptake, whereas those IL-7 GROα volume after covariate adjustment false discovery rate correction. Conclusions are deposition rather than dysfunction or atrophy. Moreover, may play important roles early-stage AD pathophysiology.

Language: Английский

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The effect of C-reactive protein and interleukin-3 on mild cognitive impairment with APOE ɛ4

Journal of Alzheimer s Disease, Journal Year: 2025, Volume and Issue: unknown

Published: April 22, 2025

Background The apolipoprotein E ε4 allele ( APOE ε4) and inflammation are associated with Alzheimer's disease (AD) pathology. Mild cognitive impairment (MCI) is considered the preclinical early stage of AD. However, comprehensive effects inflammatory mediators on MCI patients specific genotypes remain poorly understood. Objective Our study aimed to explore how different numbers alleles affect plasma C-reactive protein (CRP) interleukin-3 (IL-3) levels their associations brain structure. Methods A total 339 from Disease Neuroimaging Initiative were enrolled. We compared concentrations CRP IL-3, performance, cerebrospinal fluid (CSF) AD biomarkers across genotypes. Structural magnetic resonance imaging was utilized measure gray matter volume outcomes. Pearson correlation analysis used between above indicators. Results Plasma increased in carriers, but IL-3 expression notably decreased, homozygous state most significant. negative several abilities observed only homozygotes. Additionally, a positive scores, CSF biomarker confirmed Imaging data demonstrated that right middle frontal gyrus non-carriers. Conclusions peripheral mediators’ effect function structure differs based carrier status.

Language: Английский

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