Identification of immune microenvironment subtypes and signature genes for Alzheimer’s disease diagnosis and risk prediction based on explainable machine learning DOI Creative Commons

Yongxing Lai,

Peiqiang Lin,

Fan Lin

et al.

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Dec. 8, 2022

Background Using interpretable machine learning, we sought to define the immune microenvironment subtypes and distinctive genes in AD. Methods ssGSEA, LASSO regression, WGCNA algorithms were used evaluate state AD patients. To predict fate of identify genes, six learning developed. The output models was interpreted using SHAP LIME algorithms. For external validation, four separate GEO databases used. We estimated subgroups immunological unsupervised clustering. Further research done on variations microenvironment, enhanced functions pathways, therapeutic medicines between these subtypes. Finally, expression characteristic verified AlzData pan-cancer RT-PCR analysis. Results It determined that is connected changes microenvironment. revealed 31 potential which greenyellow blue modules shown be most associated with infiltrated cells. In testing set, XGBoost algorithm had best performance an AUC 0.86 a P-R value 0.83. Following screening set by verification independent datasets, five (CXCR4, PPP3R1, HSP90AB1, CXCL10, S100A12) closely pathological biomarkers allowed for accurate prediction progression found microenvironment-related genes. feature gene-based nomogram may provide clinical advantages Two patients identified, subtype2 linked metabolic phenotype, subtype1 belonged immune-active kind. MK-866 arachidonyltrifluoromethane identified as top treatment agents 1 2, respectively. These distinguishing intimately development disease, according Alzdata database, research, Conclusion hub are strongly pathology CXCR4, S100A12. hypothesized molecular might offer novel perceptions individualized treatment.

Language: Английский

Hallmarks of neurodegenerative diseases DOI Creative Commons

David M. Wilson,

Mark Cookson, Ludo Van Den Bosch

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(4), P. 693 - 714

Published: Feb. 1, 2023

Summary

Decades of research have identified genetic factors and biochemical pathways involved in neurodegenerative diseases (NDDs). We present evidence for the following eight hallmarks NDD: pathological protein aggregation, synaptic neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA RNA defects, inflammation, cell death. describe hallmarks, their biomarkers, interactions as a framework to study NDDs using holistic approach. The can serve basis defining pathogenic mechanisms, categorizing different based on primary stratifying patients within specific NDD, designing multi-targeted, personalized therapies effectively halt NDDs.

Language: Английский

Citations

801
Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission DOI
Gill Livingston, Jonathan Huntley, Kathy Liu

et al.

The Lancet, Journal Year: 2024, Volume and Issue: 404(10452), P. 572 - 628

Published: July 31, 2024

Language: Английский

Citations

559
Microbiota in neuroinflammation and synaptic dysfunction: a focus on Alzheimer’s disease DOI Creative Commons
Diane Bairamian, Sha Sha, Nathalie Rolhion

et al.

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: March 5, 2022

The implication of gut microbiota in the control brain functions health and disease is a novel, currently emerging concept. Accumulating data suggest that exert its action at least part by modulating neuroinflammation. Given link between neuroinflammatory changes neuronal activity, it plausible may affect indirectly impacting microglia, key player Indeed, increasing evidence suggests interplay microglia synaptic dysfunction involve microbiota, among other factors. In addition to these indirect microglia-dependent actions on has been recently recognized could also activity directly stimulation vagus nerve.

Language: Английский

Citations

202
The neuroimmune axis of Alzheimer’s disease DOI Creative Commons
Mehdi Jorfi,

Anna Maaser-Hecker,

Rudolph E. Tanzi

et al.

Genome Medicine, Journal Year: 2023, Volume and Issue: 15(1)

Published: Jan. 26, 2023

Abstract Alzheimer’s disease (AD) is a genetically complex and heterogeneous disorder with multifaceted neuropathological features, including β-amyloid plaques, neurofibrillary tangles, neuroinflammation. Over the past decade, emerging evidence has implicated both beneficial pathological roles for innate immune genes cells, peripheral cells such as T which can infiltrate brain either ameliorate or exacerbate AD neuropathogenesis. These findings support neuroimmune axis of AD, in interplay adaptive systems inside outside critically impacts etiology pathogenesis AD. In this review, we discuss complexities neuropathology at levels genetics cellular physiology, highlighting signaling pathways associated risk interactions among brain. We emphasize role mechanisms by monocytes, influence neuropathology, microglial clearance amyloid-β peptide, key component plaque cores, pro-inflammatory cytotoxic activity microglia, astrogliosis, their vasculature. Finally, review challenges outlook establishing immune-based therapies treating preventing

Language: Английский

Citations

170
Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation DOI Creative Commons
Yijun Chen, Yang Yu

Journal of Neuroinflammation, Journal Year: 2023, Volume and Issue: 20(1)

Published: July 14, 2023

Abstract Alzheimer’s Disease (AD) contributes to most cases of dementia. Its prominent neuropathological features are the extracellular neuritic plaques and intercellular neurofibrillary tangles composed aggregated β-amyloid (Aβ) hyperphosphorylated tau protein, respectively. In past few decades, disease-modifying therapy targeting Aβ has been focus AD drug development. Even though it is encouraging that two these drugs have recently received accelerated US Food Drug Administration approval for treatment, their efficacy or long-term safety controversial. Tau increasing attention as a potential therapeutic target, since evidence indicates pathology more associated with cognitive dysfunction. Moreover, inflammation, especially neuroinflammation, accompanies pathological processes also linked deficits. Accumulating inflammation complex tight interplay pathology. Here, we review recent on interaction between pathology, focusing post-translational modification dissemination, neuroinflammatory responses, including glial cell activation inflammatory signaling pathways. Then, summarize latest clinical trials neuroinflammation. Sustained increased responses in cells neurons pivotal cellular drivers regulators exacerbation which further its worsening by aggravating responses. Unraveling precise mechanisms underlying relationship neuroinflammation will provide new insights into discovery translation targets other tau-related diseases (tauopathies). Targeting multiple pathologies precision strategies be crucial direction developing tauopathies.

Language: Английский

Citations

153
Impaired insulin signalling and allostatic load in Alzheimer disease DOI
Fernanda G. De Felice, Rafaella A. Gonçalves, Sérgio T. Ferreira

et al.

Nature reviews. Neuroscience, Journal Year: 2022, Volume and Issue: 23(4), P. 215 - 230

Published: Feb. 28, 2022

Language: Английский

Citations

126
Microbiota from Alzheimer’s patients induce deficits in cognition and hippocampal neurogenesis DOI Creative Commons
Stefanie Grabrucker, Moira Marizzoni, Edina Silajdžić

et al.

Brain, Journal Year: 2023, Volume and Issue: 146(12), P. 4916 - 4934

Published: Oct. 18, 2023

Alzheimer's disease is a complex neurodegenerative disorder leading to decline in cognitive function and mental health. Recent research has positioned the gut microbiota as an important susceptibility factor by showing specific alterations microbiome composition of patients rodent models. However, it unknown whether are causal manifestation symptoms. To understand involvement patient host physiology behaviour, we transplanted faecal from age-matched healthy controls into microbiota-depleted young adult rats. We found impairments behaviours reliant on hippocampal neurogenesis, essential process for certain memory functions mood, resulting transplants. Notably, severity correlated with clinical scores donor patients. Discrete changes rat caecal metabolome were also evident. As neurogenesis cannot be measured living humans but modulated circulatory systemic environment, assessed impact environment proxy readouts. Serum decreased human cells vitro associated key microbial genera. Our findings reveal first time, that symptoms can transferred organism via microbiota, confirming role disease, highlight converging central cellular regulating gut-mediated factors Alzheimer's.

Language: Английский

Citations

114
Infiltrating CD8+ T cells exacerbate Alzheimer’s disease pathology in a 3D human neuroimmune axis model DOI
Mehdi Jorfi, Joseph Park,

Clare K. Hall

et al.

Nature Neuroscience, Journal Year: 2023, Volume and Issue: 26(9), P. 1489 - 1504

Published: Aug. 24, 2023

Language: Английский

Citations

93
Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers DOI Creative Commons
Iris E. Jansen, Sven J. van der Lee,

Duber Gomez‐Fonseca

et al.

Acta Neuropathologica, Journal Year: 2022, Volume and Issue: 144(5), P. 821 - 842

Published: Sept. 6, 2022

Abstract Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by European Alzheimer & Dementia Biobank (EADB), largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total 13,116 individuals (discovery n = 8074; replication 5042 individuals). Besides APOE locus, novel associations two other well-established AD risk loci were observed; CR1 shown locus for Aβ42 BIN1 pTau. GMNC C16orf95 further identified as pTau, which latter is novel. Clustering methods exploring influence all known protein levels, revealed 4 biological categories suggesting multiple pTau related pathways involved etiology AD. In functional follow-up analyses, both associated lateral ventricular volume, implying an overlap genetic brain volume.

Language: Английский

Citations

85
Exercise suppresses neuroinflammation for alleviating Alzheimer’s disease DOI Creative Commons
Minghui Wang, Hu Zhang, Jiling Liang

et al.

Journal of Neuroinflammation, Journal Year: 2023, Volume and Issue: 20(1)

Published: March 19, 2023

Abstract Alzheimer’s disease (AD) is a chronic neurodegenerative disease, with the characteristics of neurofibrillary tangle (NFT) and senile plaque (SP) formation. Although great progresses have been made in clinical trials based on relevant hypotheses, these studies are also accompanied by emergence toxic side effects, it an urgent task to explore underlying mechanisms for benefits prevent treat AD. Herein, animal experiments few trials, neuroinflammation AD characterized long-term activation pro-inflammatory microglia NOD-, LRR- pyrin domain-containing protein 3 (NLRP3) inflammasomes. Damaged signals from periphery within brain continuously activate microglia, thus resulting constant source inflammatory responses. The response exacerbates endoplasmic reticulum oxidative stress which triggers microglia-dependent immune responses, ultimately leading occurrence deterioration In this review, we systematically summarized sorted out that exercise ameliorates directly indirectly regulating central nervous system promoting hippocampal neurogenesis provide new direction exploring activity

Language: Английский

Citations

83