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

и другие.

Frontiers in Immunology, Год журнала: 2022, Номер 13

Опубликована: Дек. 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.

Язык: Английский

Hallmarks of neurodegenerative diseases DOI Creative Commons

David M. Wilson,

Mark Cookson, Ludo Van Den Bosch

и другие.

Cell, Год журнала: 2023, Номер 186(4), С. 693 - 714

Опубликована: Фев. 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.

Язык: Английский

Процитировано

873
Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission DOI
Gill Livingston, Jonathan Huntley, Kathy Liu

и другие.

The Lancet, Год журнала: 2024, Номер 404(10452), С. 572 - 628

Опубликована: Июль 31, 2024

Язык: Английский

Процитировано

708
Microbiota in neuroinflammation and synaptic dysfunction: a focus on Alzheimer’s disease DOI Creative Commons
Diane Bairamian, Sha Sha, Nathalie Rolhion

и другие.

Molecular Neurodegeneration, Год журнала: 2022, Номер 17(1)

Опубликована: Март 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.

Язык: Английский

Процитировано

212
The neuroimmune axis of Alzheimer’s disease DOI Creative Commons
Mehdi Jorfi,

Anna Maaser-Hecker,

Rudolph E. Tanzi

и другие.

Genome Medicine, Год журнала: 2023, Номер 15(1)

Опубликована: Янв. 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

Язык: Английский

Процитировано

174
Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation DOI Creative Commons
Yijun Chen, Yang Yu

Journal of Neuroinflammation, Год журнала: 2023, Номер 20(1)

Опубликована: Июль 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.

Язык: Английский

Процитировано

167
Impaired insulin signalling and allostatic load in Alzheimer disease DOI
Fernanda G. De Felice, Rafaella A. Gonçalves, Sérgio T. Ferreira

и другие.

Nature reviews. Neuroscience, Год журнала: 2022, Номер 23(4), С. 215 - 230

Опубликована: Фев. 28, 2022

Язык: Английский

Процитировано

130
Microbiota from Alzheimer’s patients induce deficits in cognition and hippocampal neurogenesis DOI Creative Commons
Stefanie Grabrucker, Moira Marizzoni, Edina Silajdžić

и другие.

Brain, Год журнала: 2023, Номер 146(12), С. 4916 - 4934

Опубликована: Окт. 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.

Язык: Английский

Процитировано

122
Infiltrating CD8+ T cells exacerbate Alzheimer’s disease pathology in a 3D human neuroimmune axis model DOI
Mehdi Jorfi, Joseph Park,

Clare K. Hall

и другие.

Nature Neuroscience, Год журнала: 2023, Номер 26(9), С. 1489 - 1504

Опубликована: Авг. 24, 2023

Язык: Английский

Процитировано

100
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

и другие.

Acta Neuropathologica, Год журнала: 2022, Номер 144(5), С. 821 - 842

Опубликована: Сен. 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.

Язык: Английский

Процитировано

87
Current understanding of the Alzheimer’s disease-associated microbiome and therapeutic strategies DOI Creative Commons
Dong-oh Seo, David M. Holtzman

Experimental & Molecular Medicine, Год журнала: 2024, Номер 56(1), С. 86 - 94

Опубликована: Янв. 4, 2024

Abstract Alzheimer’s disease (AD) is a fatal progressive neurodegenerative disease. Despite tremendous research efforts to understand this complex disease, the exact pathophysiology of not completely clear. Recently, anti-Aβ antibodies have been shown remove amyloid from brain and slow clinical progression mild dementia by ~30%. However, exploring alternative strategies crucial understanding developing more effective therapeutic interventions. In recent years, microbiota-gut-brain axis has received significant attention in AD field. Numerous studies suggested that alterations gut microbiota composition are associated with AD, several underlying mechanisms proposed. area still their infancy, many aspects field just beginning be explored understood. Gaining deeper intricate interactions signaling pathways involved microbiota-AD interaction for optimizing targeting positively impact AD. review, we aim summarize current We will discuss existing evidence regarding role pathogenesis, mechanisms, biological factors influencing microbiome-gut-brain remaining questions Last, potential approaches recondition community alleviate progression. An ongoing exploration gut-brain development microbiota-based therapies hold advancing management future.

Язык: Английский

Процитировано

87