Depletion of NK Cells Improves Cognitive Function in the Alzheimer Disease Mouse Model

Zhang, Yuanyue; Fung, Ivan Ting Hin; Sankar, Poornima; Chen, Xiangyu; Robison, Lisa S.; Ye, Long‐Yun; D’Souza, Shanti S.; Salinero, Abigail E.; Kuentzel, Marcy; Chittur, Sridar V.; Zhang, Wenzheng; Zuloaga, Kristen L.; Yang, Qi

doi:10.4049/jimmunol.2000037

Cited by 59 publications

(58 citation statements)

References 63 publications

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“…Neutrophil depletion or suppression of neutrophil trafficking ameliorated memory impairment in 3xTg-AD transgenic mice (5). Depletion of NK cells by anti-NK1.1 antibody enhanced neurogenesis, reduced neuroinflammation, and ameliorated cognitive impairment in 3xTg-AD mice (7). These studies have confirmed the interaction between peripheral immune cells and the CNS in AD.…”

Section: Introductionmentioning

confidence: 60%

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Expression of Immune Related Genes and Possible Regulatory Mechanisms in Alzheimer’s Disease

et al. 2021

Front. Immunol.

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Immune infiltration of peripheral natural killer (NK) cells in the brain has been observed in Alzheimer’s disease (AD). Immunity-related genes (IRGs) play an essential role in immune infiltration; however, the expression of IRGs and possible regulatory mechanisms involved in AD remain unclear. The peripheral blood mononuclear cells (PBMCs) single-cell RNA (scRNA) sequencing data from patients with AD were analyzed and PBMCs obtained from the ImmPort database were screened for cluster marker genes. IRG activity was calculated using the AUCell package. A bulk sequencing dataset of AD brain tissues was analyzed to explore common IRGs between PBMCs and the brain. Relevant regulatory transcription factors (TFs) were identified from the Human TFDB database. The protein-protein interaction network of key TFs were generated using the STRING database. Eight clusters were identified, including memory CD4 T, NKT, NK, B, DC, CD8 T cells, and platelets. NK cells were significantly decreased in patients with AD, while CD4 T cells were increased. NK and DC cells exhibited the highest IRG activity. GO and KEGG analyses of the scRNA and bulk sequencing data showed that the DEGs focused on the immune response. Seventy common IRGs were found in both peripheral NK cells and the brain. Seventeen TFs were associated with IRG expression, and the PPI network indicated that STAT3, IRF1, and REL were the hub TFs. In conclusion, we propose that peripheral NK cells may infiltrate the brain and contribute to neuroinflammatory changes in AD through bioinformatic analysis of scRNA and bulk sequencing data. Moreover, STAT3 may be involved in the transcriptional regulation of IRGs in NK cells.

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Section: Introductionmentioning

confidence: 60%

“…The cytotoxic activity of peripheral NK cells is impaired in aged individuals compared to that in young adults during aging (30). Circulating NK cell infiltration into the brain has been found in human AD and 3xTg-AD mice (6,7). NK cells exhibited enhanced pro-inflammatory profiles in the brains of 3xTg-AD mice.…”

Section: Discussionmentioning

confidence: 99%

Expression of Immune Related Genes and Possible Regulatory Mechanisms in Alzheimer’s Disease

et al. 2021

Front. Immunol.

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“…Ly6C + monocytes and Ly6G + neutrophils were sorted by FACS. scRNA‐seq was performed as we previously described (Fung et al, 2020 ; Harly et al, 2019 ; Zhang et al, 2020 ). scRNA‐seq libraries were generated using the chromium 5’ single‐cell gene expression kit (10x genomics) according to the manufacturer's instructions.…”

Section: Discussionmentioning

confidence: 99%

Type I Interferon signaling controls the accumulation and transcriptomes of monocytes in the aged lung

et al. 2021

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Aging is paradoxically associated with a deteriorated immune defense (immunosenescence) and increased basal levels of tissue inflammation (inflammaging). The lung is particularly sensitive to the effects of aging. The immune cell mechanisms underlying physiological lung aging remain poorly understood. Here we reveal that aging leads to increased interferon signaling and elevated concentrations of chemokines in the lung, which is associated with infiltration of monocytes into the lung parenchyma. scRNA‐seq identified a novel Type‐1 interferon signaling dependent monocyte subset (MO‐ifn) that upregulated IFNAR1 expression and exhibited greater transcriptomal changes with aging than the other monocytes. Blockade of type‐1 interferon signaling by treatment with anti‐IFNAR1 neutralizing antibodies rapidly ablated MO‐ifn cells. Treatment with anti‐IFNAR1 antibodies also reduced airway chemokine concentrations and repressed the accumulation of the overall monocyte population in the parenchyma of the aged lung. Together, our work suggests that physiological aging is associated with increased basal level of airway monocyte infiltration and inflammation in part due to elevated type‐1 interferon signaling.

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“…scRNA-seq was performed as we previously described [ 5 , 18 , 29 ]. Specifically, single-cell libraries were generated using Chromium 5” gene expression (10x Genomics) according to the manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

“…CD8 + effector memory T cells with enhanced T cell receptor (TCR) signaling accumulated in the brains of AD patients, and their numbers were negatively associated with cognitive function [ 4 ]. Depletion of NK cells, the innate lymphocyte subset with cytotoxic function, alleviated neuroinflammation and cognitive decline in the triple transgenic mouse model of AD (3xTg-AD) [ 5 ]. Nevertheless, genetic deletion of both adaptive and innate lymphocytes led to exacerbated Aβ pathology in 5xfAD mice, indicating that some other lymphocyte subsets might instead play a protective role in AD [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Group 2 innate lymphoid cells are numerically and functionally deficient in the triple transgenic mouse model of Alzheimer’s disease

Fung

Zhang

Shin

et al. 2021

J Neuroinflammation

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Background The immune pathways in Alzheimer’s disease (AD) remain incompletely understood. Our recent study indicates that tissue-resident group 2 innate lymphoid cells (ILC2) accumulate in the brain barriers of aged mice and that their activation alleviates aging-associated cognitive decline. The regulation and function of ILC2 in AD, however, remain unknown. Methods In this study, we examined the numbers and functional capability of ILC2 from the triple transgenic AD mice (3xTg-AD) and control wild-type mice. We investigated the effects of treatment with IL-5, a cytokine produced by ILC2, on the cognitive function of 3xTg-AD mice. Results We demonstrate that brain-associated ILC2 are numerically and functionally defective in the triple transgenic AD mouse model (3xTg-AD). The numbers of brain-associated ILC2 were greatly reduced in 7-month-old 3xTg-AD mice of both sexes, compared to those in age- and sex-matched control wild-type mice. The remaining ILC2 in 3xTg-AD mice failed to efficiently produce the type 2 cytokine IL-5 but gained the capability to express a number of proinflammatory genes. Administration of IL-5, a cytokine produced by ILC2, transiently improved spatial recognition and learning in 3xTg-AD mice. Conclusion Our results collectively indicate that numerical and functional deficiency of ILC2 might contribute to the cognitive impairment of 3xTg-AD mice.

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Depletion of NK Cells Improves Cognitive Function in the Alzheimer Disease Mouse Model

Cited by 59 publications

References 63 publications

Expression of Immune Related Genes and Possible Regulatory Mechanisms in Alzheimer’s Disease

Expression of Immune Related Genes and Possible Regulatory Mechanisms in Alzheimer’s Disease

Type I Interferon signaling controls the accumulation and transcriptomes of monocytes in the aged lung

Group 2 innate lymphoid cells are numerically and functionally deficient in the triple transgenic mouse model of Alzheimer’s disease

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