Neuroblast senescence in the aged brain augments natural killer cell cytotoxicity leading to impaired neurogenesis and cognition

Jin, Wei‐Na; Shi, Kaibin; He, Wenyan; Sun, Jun-hong; Kaer, Luc Van; Shi, Fu‐Dong; Liu, Qiang

doi:10.1038/s41593-020-00745-w

Cited by 122 publications

(123 citation statements)

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“…In addition to intrinsic changes, neurogenesis is profoundly influenced by the neurogenic niche, which is comprised of microglia, oligodendrocytes, neurovasculature, and the systemic cytokine and chemokine environment (Kempermann et al, 2015 ). It has been reported that neuroinflammation is a known negative regulator of adult hippocampal neurogenesis (Fan et al, 2017 ; Jin et al, 2021 ; Leng and Edison, 2021 ), in which age-induced microglia activation and pro-inflammatory factors play a central role (Leng and Edison, 2021 ). Through analysis of age-related DEGs, we observed that upregulated genes were enriched for “regulation of chemokine” and “chemokine production” in the aged cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Single-nucleus transcriptomic landscape of primate hippocampal aging

Zhang

Ren

et al. 2021

Protein &Amp; Cell

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The hippocampus plays a crucial role in learning and memory, and its progressive deterioration with age is functionally linked to a variety of human neurodegenerative diseases. Yet a systematic profiling of the aging effects on various hippocampal cell types in primates is still missing. Here, we reported a variety of new aging-associated phenotypic changes of the primate hippocampus. These include, in particular, increased DNA damage and heterochromatin erosion with time, alongside loss of proteostasis and elevated inflammation. To understand their cellular and molecular causes, we established the first single-nucleus transcriptomic atlas of primate hippocampal aging. Among the 12 identified cell types, neural transiently amplifying progenitor cell (TAPC) and microglia were most affected by aging. In-depth dissection of gene-expression dynamics revealed impaired TAPC division and compromised neuronal function along the neurogenesis trajectory; additionally elevated pro-inflammatory responses in the aged microglia and oligodendrocyte, as well as dysregulated coagulation pathways in the aged endothelial cells may contribute to a hostile microenvironment for neurogenesis. This rich resource for understanding primate hippocampal aging may provide potential diagnostic biomarkers and therapeutic interventions against age-related neurodegenerative diseases.

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Section: Resultsmentioning

confidence: 99%

Single-nucleus transcriptomic landscape of primate hippocampal aging

Zhang

Ren

et al. 2021

Protein &Amp; Cell

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“…Work in progress by Paramos-de-Carvalho et al suggests that, in the aged adult, neurons become senescent following inflammation from SCI and that inhibiting their depletion using a senolytic treatment may improve functional recovery (Paramos-de-Carvalho et al 2020). Indeed, neuroblast senescence in aged brains increases as it becomes more inflammatory (Jin et al 2021). Clearly, with age come innate molecular changes based on cellular transcriptional heterogeneity as well as differences in immune responses to injury and exacerbation of inflammation-induced glial scar formation (Fitch and Silver 2008).…”

Section: Changes In the Capacity Of Cns Regeneration Through Different Phyla And Across Agesmentioning

confidence: 99%

New insights into glial scar formation after spinal cord injury

2021

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Severe spinal cord injury causes permanent loss of function and sensation throughout the body. The trauma causes a multifaceted torrent of pathophysiological processes which ultimately act to form a complex structure, permanently remodeling the cellular architecture and extracellular matrix. This structure is traditionally termed the glial/fibrotic scar. Similar cellular formations occur following stroke, infection, and neurodegenerative diseases of the central nervous system (CNS) signifying their fundamental importance to preservation of function. It is increasingly recognized that the scar performs multiple roles affecting recovery following traumatic injury. Innovative research into the properties of this structure is imperative to the development of treatment strategies to recover motor function and sensation following CNS trauma. In this review, we summarize how the regeneration potential of the CNS alters across phyla and age through formation of scar-like structures. We describe how new insights from next-generation sequencing technologies have yielded a more complex portrait of the molecular mechanisms governing the astrocyte, microglial, and neuronal responses to injury and development, especially of the glial component of the scar. Finally, we discuss possible combinatorial therapeutic approaches centering on scar modulation to restore function after severe CNS injury.

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“…Natural killer (NK) cells are a type of cytotoxic lymphocyte that can infiltrate the ischemic brain and exacerbate neuronal cell death (41). Recent research indicates that NK cells play a key role in neurogenesis and cognitive decline during normal brain aging (42). It can be seen that lncRNAs may mediate the cytotoxicity of NK cells to aggravate the progression of VaD, and at the same time, the effect of NKT cells may be inhibited.…”

Section: Discussionmentioning

confidence: 99%

Construction of a ceRNA immunoregulatory network related to the development of vascular dementia through a weighted gene coexpression network analysis

et al. 2021

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Background: To date, vascular dementia (VaD) lacks effective treatment in clinical practice. There is also growing evidence that VaD may be closely related to the immune response. The development of highthroughput technology, and the recently discovered group of new mediators called competitive endogenous RNAs (ceRNA), provides a unique opportunity to study the immunomodulation of VaD.Methods: In this study, we used gene expression profiles in the Gene Expression Omnibus (GEO) database to obtain immune-related gene coexpression modules through a weighted gene coexpression network analysis (WGCNA) and gene enrichment analysis. We extracted and merged long non-coding RNA (lncRNA) and microRNA (miRNA) expressions from the GEO database and mapped them with related databases.Subsequently, we used Cytoscape to construct a lncRNA-miRNA-mRNA network, and then we performed an enrichment analysis on the mRNAs in the network to determine their regulatory function. Subsequently, we used an ImmuCellAI immune infiltration analysis and constructed a ceRNA sub-network of related immune cells. Finally, we conducted a gene set enrichment analysis (GSEA) to determine the potential regulatory pathways of the key factors.Results: As a result, we identified the blue module as the key module of immunity and constructed the related CeRNA network. Immune infiltration analysis showed that natural killer T (NKT) cells may be the key immune cells of VaD. Using a Pearson correlation analysis, we identified that B4GALT1, PPP1R3B, MICB, HHAT, DSC2, DNA2, SCARA3, and lncRNA NEAT1 may be the key factors of VaD. Our subsequent GSEA analysis showed that lncRNA NEAT1 may be regulated by NK cells and toll-like receptors.Conclusions: Our research provides new therapeutic targets for vascular dementia from the immunological perspective for the first time, including B4GALT1, PPP1R3B, MICB, HHAT, DSC2, DNA2, SCARA3, and lncRNA NEAT1, and our research hopes to provide new treatment options for VaD.

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Neuroblast senescence in the aged brain augments natural killer cell cytotoxicity leading to impaired neurogenesis and cognition

Cited by 122 publications

References 50 publications

Single-nucleus transcriptomic landscape of primate hippocampal aging

Single-nucleus transcriptomic landscape of primate hippocampal aging

New insights into glial scar formation after spinal cord injury

Construction of a ceRNA immunoregulatory network related to the development of vascular dementia through a weighted gene coexpression network analysis

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