T cell aging and Alzheimer’s disease

Guo, Lin; Li, Xiaoting; Gould, Timothy M.; Wang, Zhan-You; Cao, Wenqiang

doi:10.3389/fimmu.2023.1154699

Cited by 14 publications

(9 citation statements)

References 102 publications

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“…Peripheral immune disorders and peripheral-central immune crosstalk have been investigated for their important roles in the pathogenesis and progression of AD [ 8 ]. Several researchers have demonstrated cytotoxic effects of CD8 + efferent memory CD45RA + (T EMRA ) cells, Th1 and Th17 in CD4 T cells in AD pathology, which is consistent with our study [ 57 , 58 ]. Natural killer (NK) T cells have the ability to rapidly induce cell apoptosis through cytotoxic granules and release of inflammatory factors such as TNF-α, INF-γ.…”

Section: Discussionsupporting

confidence: 93%

Identification of mitochondrial related signature associated with immune microenvironment in Alzheimer’s disease

et al. 2023

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Background Alzheimer's disease (AD) is the most common neurodegenerative disease. Mitochondrial dysfunction and immune responses are important factors in the pathogenesis of AD, but their crosstalk in AD has not been studied. In this study, the independent role and interaction of mitochondria-related genes and immune cell infiltration in AD were investigated using bioinformatics methods. Methods The datasets of AD were obtained from NCBI Gene Expression Omnibus (GEO), and the data of mitochondrial genes was from MitoCarta3.0 database. Subsequently, differential expression genes (DEGs) screening and GSEA functional enrichment analysis were performed. The intersection of DEGs and mitochondrial related genes was used to obtain MitoDEGs. The MitoDEGs most relevant to AD were determined by Least absolute shrinkage and selection operator and multiple support vector machine recursive feature elimination, as well as protein–protein interactions (PPI) network and random forest. The infiltration of 28 kinds of immune cells in AD was analyzed by ssGSEA, and the relationship between hub MitoDEGs and the proportion of immune infiltration was studied. The expression levels of hub MitoDEGs were verified in cell models and AD mice, and the role of OPA1 in mitochondrial damage and neuronal apoptosis was investigated. Results The functions and pathways of DEGs were significantly enriched in AD, including immune response activation, IL1R pathway, mitochondrial metabolism, oxidative damage response and electron transport chain-oxphos system in mitochondria. Hub MitoDEGs closely related to AD were obtained based on PPI network, random forest and two machine learning algorithms. Five hub MitoDEGs associated with neurological disorders were identified by biological function examination. The hub MitoDEGs were found to be correlated with memory B cell, effector memory CD8 T cell, activated dendritic cell, natural killer T cell, type 17 T helper cell, Neutrophil, MDSC, plasmacytoid dendritic cell. These genes can also be used to predict the risk of AD and have good diagnostic efficacy. In addition, the mRNA expression levels of BDH1, TRAP1, OPA1, DLD in cell models and AD mice were consistent with the results of bioinformatics analysis, and expression levels of SPG7 showed a downward trend. Meanwhile, OPA1 overexpression alleviated mitochondrial damage and neuronal apoptosis induced by Aβ1-42. Conclusions Five potential hub MitoDEGs most associated with AD were identified. Their interaction with immune microenvironment may play a crucial role in the occurrence and prognosis of AD, which provides a new insight for studying the potential pathogenesis of AD and exploring new targets.

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Section: Discussionsupporting

confidence: 93%

Identification of mitochondrial related signature associated with immune microenvironment in Alzheimer’s disease

et al. 2023

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“…Neuronal damage directs CNS tissue regeneration through neuronal stem cell (NSC) and microglial proliferation however, microglial activation can also inhibit CNS regeneration( 97, 108–110 ). Aging is known to decrease regenerative NSCs and increase senescent microglia and T cells that secrete pro-inflammatory cytokines( 97, 100, 109, 111–113 ). In AD and PD, age-dependent accumulation of senescent NSCs and microglia were associated with a severe proinflammatory state( 100, 111 ).…”

Section: Discussionmentioning

confidence: 99%

“…Aging is known to decrease regenerative NSCs and increase senescent microglia and T cells that secrete pro-inflammatory cytokines( 97, 100, 109, 111–113 ). In AD and PD, age-dependent accumulation of senescent NSCs and microglia were associated with a severe proinflammatory state( 100, 111 ). Cytokine responses in the CNS of POWV infected 50 week old mice reflect induced senescent cell cytokines (TNFα, IL6, IL-1β) that may contribute to an age-dependent senescence associated secretory phenotype (SASP)( 2, 13, 16, 103, 105, 114 ).…”

Section: Discussionmentioning

confidence: 99%

Age-dependent Powassan Virus Lethality is Directed by Glial Cell Activation and Divergent Neuroinflammatory Cytokine Responses in a Murine Model

Mladinich,

Himmler,

Conde

et al. 2023

Preprint

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Powassan virus (POWV) is an emergent tick-borne flavivirus that causes fatal encephalitis in the elderly and long-term neurologic sequelae in survivors. How age contributes to severe POWV encephalitis remains an enigma and there are currently no animal models that reflect age-dependent POWV neuropathology. Inoculating C57BL/6 mice with a POWV strain (LI9) currently circulating inIxodesticks, resulted in age-dependent POWV lethality with overt spongiform brain damage 10-15 dpi. Infection of 50 week old mice resulted in 82% lethality 10-15 dpi that was sequentially reduced by age to 7.1% in 10 week old mice. LI9 encephalitis resulted in early neuronal depletion, with severe CNS damage, persistent inflammatory gliosis and long-term spongiform pathology in survivors (30 dpi). In all mice POWV LI9 was neuroinvasive and reached maximum POWV loads in the CNS 10 dpi. Coincident with murine lethality, in 50 week old mice maximum POWV CNS levels persisted 15 dpi, while instead decreasing by 2-4 logs in 10-30 week old mice. Although glial cells were highly activated in all POWV infected mice, differences in age-dependent CNS cytokine responses were striking 15 dpi. In 50 week old mice POWV induced Th1-type cytokines (IFNγ, IL-2, IL-12, IL-4, TNFα, IL-6), suggesting a pro-inflammatory M1 microglial activation cascade. In contrast, POWV induced Th2-type cytokines (IL-10, TGFβ, IL-4) in 10 week old mice consistent with a neuroprotective M2 microglial phenotype. These findings reflect differences in neurodegenerative versus neuroprotective glial cell responses that correlate with divergent CNS viral clearance and age-dependent POWV LI9 lethality. Discrete age-dependent CNS cytokine responses suggest neuroinflammatory targets as potential POWV therapeutics. These studies establish a highly lethal POWV murine model and reveal a hyperinflammatory mechanism of age-dependent POWV lethality that mirrors human POWV severity and long-term CNS sequelae in the elderly.ImportancePowassan virus is an emerging tick-borne flavivirus causing lethal encephalitis in aged individuals. We reveal an age-dependent POWV murine model that mirrors human POWV encephalitis and long-term CNS damage in the elderly. Findings demonstrate that POWV load and discrete glial cell cytokine responses in the CNS are critical determinants of age-dependent POWV lethality. POWV age-independently activates microglia and astrocytes, but directs neuroprotective Th2 cytokine responses in 10 week old mice and distinct pro-inflammatory Th1 cytokine responses in the CNS of 50 week old mice. This reveals roles for a hyperinflammatory CNS cytokine cascade in age-dependent POWV lethality, and protective anti-inflammatory cytokines in murine survival. Notably, results define potential therapeutic targets and rationalize approaches for preventing severe POWV encephalitis that may be broadly applicable to neurodegenerative diseases. This age-dependent murine POWV model permits analysis of vaccines, and therapeutics that prevent POWV neuroinvasion or resolve severe POWV encephalitis in the elderly.

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“…Studies in human patients and mouse models highlighted the potential role and dysfunction of peripheral T cells in AD ( Dai and Shen, 2021 ; Guo et al, 2023 ). Recent studies have shown an increased infiltration of T cells into the brain of old mice and in the plaque-harboring cortex of AD-prone mice ( Mrdjen et al, 2018 ).…”

Section: Meningeal T Cells Behavior During Neuroinflammation and Neur...mentioning

confidence: 99%

Meningeal T cells function in the central nervous system homeostasis and neurodegenerative diseases

Abbaoui

Fatoba

Yamashita

2023

Front. Cell. Neurosci.

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Recently, a rising interest is given to neuroimmune communication in physiological and neuropathological conditions. Meningeal immunity is a complex immune environment housing different types of immune cells. Here, we focus on meningeal T cells, possibly the most explored aspect of neuro-immune cell interactions. Emerging data have shown that meningeal T cells play a crucial role in the pathogenesis of several neurodegenerative disorders, including multiple sclerosis, Alzheimer’s, Parkinson’s, and Huntington’s diseases. This review highlights how meningeal T cells may contribute to immune surveillance of the central nervous system (CNS) and regulate neurobehavioral functions through the secretion of cytokines. Overall, this review assesses the recent knowledge of meningeal T cells and their effects on CNS functioning in both health and disease conditions and the underlying mechanisms.

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T cell aging and Alzheimer’s disease

Cited by 14 publications

References 102 publications

Identification of mitochondrial related signature associated with immune microenvironment in Alzheimer’s disease

Identification of mitochondrial related signature associated with immune microenvironment in Alzheimer’s disease

Age-dependent Powassan Virus Lethality is Directed by Glial Cell Activation and Divergent Neuroinflammatory Cytokine Responses in a Murine Model

Meningeal T cells function in the central nervous system homeostasis and neurodegenerative diseases

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