Insights into T‐cell dysfunction in Alzheimer's disease

Dai, Linbin; Shen, Yong

doi:10.1111/acel.13511

Cited by 50 publications

(49 citation statements)

References 238 publications

(232 reference statements)

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“…The abundance of immune cells were altered between control subjects and patients with AD. AD patients exhibited higher infiltration levels of B cells, T cells, neutrophils, resting NK cells, and macrophages, which were consensus with the previous studies verified in blood or brain tissues (Dey and Hankey Giblin, 2018 ; Dai and Shen, 2021 ; Paranjpe et al, 2021 ; Wang et al, 2022a ). Further, we utilized unsupervised cluster analysis to illustrate the different cuproptosis regulation patterns in AD patients based on the expression landscapes of CRGs, and two distinct cuproptosis-related clusters were identified.…”

Section: Discussionsupporting

confidence: 91%

Identification and immunological characterization of cuproptosis-related molecular clusters in Alzheimer's disease

Lai

Lin

et al. 2022

Front. Aging Neurosci.

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IntroductionAlzheimer's disease is the most common dementia with clinical and pathological heterogeneity. Cuproptosis is a recently reported form of cell death, which appears to result in the progression of various diseases. Therefore, our study aimed to explore cuproptosis-related molecular clusters in Alzheimer's disease and construct a prediction model.MethodsBased on the GSE33000 dataset, we analyzed the expression profiles of cuproptosis regulators and immune characteristics in Alzheimer's disease. Using 310 Alzheimer's disease samples, we explored the molecular clusters based on cuproptosis-related genes, along with the related immune cell infiltration. Cluster-specific differentially expressed genes were identified using the WGCNA algorithm. Subsequently, the optimal machine model was chosen by comparing the performance of the random forest model, support vector machine model, generalized linear model, and eXtreme Gradient Boosting. Nomogram, calibration curve, decision curve analysis, and three external datasets were applied for validating the predictive efficiency.ResultsThe dysregulated cuproptosis-related genes and activated immune responses were determined between Alzheimer's disease and non-Alzheimer's disease controls. Two cuproptosis-related molecular clusters were defined in Alzheimer's disease. Analysis of immune infiltration suggested the significant heterogeneity of immunity between distinct clusters. Cluster2 was characterized by elevated immune scores and relatively higher levels of immune infiltration. Functional analysis showed that cluster-specific differentially expressed genes in Cluster2 were closely related to various immune responses. The Random forest machine model presented the best discriminative performance with relatively lower residual and root mean square error, and a higher area under the curve (AUC = 0.9829). A final 5-gene-based random forest model was constructed, exhibiting satisfactory performance in two external validation datasets (AUC = 0.8529 and 0.8333). The nomogram, calibration curve, and decision curve analysis also demonstrated the accuracy to predict Alzheimer's disease subtypes. Further analysis revealed that these five model-related genes were significantly associated with the Aβ-42 levels and β-secretase activity.ConclusionOur study systematically illustrated the complicated relationship between cuproptosis and Alzheimer's disease, and developed a promising prediction model to evaluate the risk of cuproptosis subtypes and the pathological outcome of Alzheimer's disease patients.

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Section: Discussionsupporting

confidence: 91%

Identification and immunological characterization of cuproptosis-related molecular clusters in Alzheimer's disease

Lai

Lin

et al. 2022

Front. Aging Neurosci.

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“…Lymphocytes are known to be involved in AD; for instance, T cells infiltrate the CNS in AD with a potential role in disease pathology 50 and directly interact with neurons and promote neuroinflammation. 51 Due to the small size of the clusters C1 and C11, it is difficult to interpret these findings in the context of resilience. Further studies with enrichment of these cell types would be necessary to determine their role in resilience.…”

Section: Resultsmentioning

confidence: 99%

Conserved cell-type specific signature of resilience to Alzheimer’s disease nominates role for excitatory intratelencephalic cortical neurons

Telpoukhovskaia

Hadad

Gurdon

et al. 2022

Preprint

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Alzheimer’s disease (AD), the leading cause of dementia, affects millions of people worldwide. With no disease-modifying medication currently available, the human toll and economic costs are rising rapidly. Under current standards, a patient is diagnosed with AD when both cognitive decline and pathology (amyloid plaques and neurofibrillary tangles) are present. Remarkably, some individuals who have AD pathology remain cognitively normal. Uncovering factors that lead to “cognitive resilience” to AD is a promising path to create new targets for therapies. However, technical challenges discovering novel human resilience factors limit testing, validation, and nomination of novel drugs for AD. In this study, we use single-nuclear transcriptional profiles of postmortem cortex from human individuals with high AD pathology who were either cognitively normal (resilient) or cognitively impaired (susceptible) at time of death, as well as mouse strains that parallel these differences in cognition with high amyloid. Our cross-species discovery approach highlights a novel role for excitatory layer 4/5 cortical neurons in promoting cognitive resilience to AD, and nominates several resilience genes that include ATP1A1, GABRB1, PTK2, and ROCK2. Nominated resilience genes were tested for replication in orthogonal data sets and confirmed to be correlated with cognitive resilience. Additionally, we identified several potential mechanisms of resilience, including regulation of membrane potential, axonal and dendritic growth, and general increase of protein cycle, potentially of membrane proteins. Because our discovery of resilience-associated genes in layer 4/5 cortical neurons originates from an integrated human and mouse transcriptomic space from susceptible and resilient individuals, we are positioned to test causality and perform mechanistic, validation, and pre-clinical studies in our human-relevant AD-BXD mouse panel.

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“…The specific allele of the APOE protein is crucial, as individuals with the APOE4 allele have higher levels of T cell activation and a higher risk of developing AD (Bonacina et al, 2018). As a result, this gene may be considered a potential target for controlling abnormal T cell activation in AD (Dai & Shen, 2021).…”

Section: T Cells In Alzheimer's Diseasementioning

confidence: 99%

Update on the Role of T Cells in Cognitive Impairment

Ruiz-Fernandez

Sánchez-Díaz

Ortega-Sollero

et al. 2023

Preprint

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The central nervous system (CNS) has long been considered an immune-privileged site, with minimal interaction between immune cells, particularly of the adaptive immune system. Previously, the presence of immune cells in this organ was primarily linked to events involving disruption of the blood-brain barrier (BBB) or inflammation. However, current research has shown that immune cells are found patrolling CNS under homeostatic conditions. Specifically, T cells of the adaptive immune system are able to cross the BBB and are associated with aging and cognitive impairment. In addition, T-cell infiltration has been observed in pathological conditions, where inflammation correlates with poor prognosis. Despite ongoing research, the role of this population in the aging brain under both physiological and pathological conditions is not yet fully understood. In this review, we provide an overview of the interactions between T cells and other immune and CNS parenchymal cells, and examine the molecular mechanisms by which these interactions may contribute to normal brain function and the scenarios in which disruption of these connections lead to cognitive impairment. A comprehensive understanding of the role of T cells in the aging brain and the underlying molecular pathways under normal conditions could pave the way for new research to better understand brain disorders.

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Insights into T‐cell dysfunction in Alzheimer's disease

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 50 publications

References 238 publications

Identification and immunological characterization of cuproptosis-related molecular clusters in Alzheimer's disease

Identification and immunological characterization of cuproptosis-related molecular clusters in Alzheimer's disease

Conserved cell-type specific signature of resilience to Alzheimer’s disease nominates role for excitatory intratelencephalic cortical neurons

Update on the Role of T Cells in Cognitive Impairment

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