SerpinA3N deficiency deteriorates impairments of learning and memory in mice following hippocampal stab injury

Wang, Zhimeng; Liu, Cong; Wang, Yingying; Deng, Yu-Sen; He, Xuan-Cheng; Du, Heng; Liu, Chang‐Mei; Teng, Zhao‐Qian

doi:10.1038/s41420-020-00325-8

Cited by 24 publications

(27 citation statements)

References 49 publications

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“…Consistent with our microglial RNAseq data, this also did not co-localize with IBA1. Neurons and oligodendrocytes have both been demonstrated to upregulate Serpina3n expression in the setting of CNS injury, making it likely that these cell types account for the Serpina3n expression that did not co-localize with GFAP in our experiments [ 31 , 32 ]. Overall, the data obtained from our combined fluorescent in situ hybridization and immunofluorescence experiments validated the lineage-specific gene expression changes detected by RNAseq and provided information on the spatial distribution of the genes examined.…”

Section: Resultsmentioning

confidence: 99%

Traumatic brain injury results in unique microglial and astrocyte transcriptomes enriched for type I interferon response

Todd

Chimenti

Luo

et al. 2021

J Neuroinflammation

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Background Traumatic brain injury (TBI) is a leading cause of death and disability that lacks neuroprotective therapies. Following a TBI, secondary injury response pathways are activated and contribute to ongoing neurodegeneration. Microglia and astrocytes are critical neuroimmune modulators with early and persistent reactivity following a TBI. Although histologic glial reactivity is well established, a precise understanding of microglia and astrocyte function following trauma remains unknown. Methods Adult male C57BL/6J mice underwent either fluid percussion or sham injury. RNA sequencing of concurrently isolated microglia and astrocytes was conducted 7 days post-injury to evaluate cell-type-specific transcriptional responses to TBI. Dual in situ hybridization and immunofluorescence were used to validate the TBI-induced gene expression changes in microglia and astrocytes and to identify spatial orientation of cells expressing these genes. Comparative analysis was performed between our glial transcriptomes and those from prior reports in mild TBI and other neurologic diseases to determine if severe TBI induces unique states of microglial and astrocyte activation. Results Our findings revealed sustained, lineage-specific transcriptional changes in both microglia and astrocytes, with microglia showing a greater transcriptional response than astrocytes at this subacute time point. Microglia and astrocytes showed overlapping enrichment for genes related to type I interferon signaling and MHC class I antigen presentation. The microglia and astrocyte transcriptional response to severe TBI was distinct from prior reports in mild TBI and other neurodegenerative and neuroinflammatory diseases. Conclusion Concurrent lineage-specific analysis revealed novel TBI-specific transcriptional changes; these findings highlight the importance of cell-type-specific analysis of glial reactivity following TBI and may assist with the identification of novel, targeted therapies.

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Section: Resultsmentioning

confidence: 99%

Traumatic brain injury results in unique microglial and astrocyte transcriptomes enriched for type I interferon response

Todd

Chimenti

Luo

et al. 2021

J Neuroinflammation

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“…One of the most robust differences observed in the NanoString panel was a serine protease inhibitor, SERPINA3N . Previous research has shown a role for SERPINA3N in neuroprotection, 47,48 with polymorphisms being associated independently with Alzheimer’s disease, 49 Parkinson’s disease, 50 and progressive multiple sclerosis. 51 SERPINA3N encodes α1-antichymotrypsin (ACT), acutely inhibits chymotrypsin and cathepsin G, serving as a modulator of inflammation and complement activation.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E ε4/4 genotype limits response to dietary induction of hyperhomocysteinemia and resulting inflammatory signaling

Seaks

Weekman

Sudduth³

et al. 2022

J Cereb Blood Flow Metab

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Vascular contributions to cognitive impairment and dementia (VCID) are the second leading cause of dementia behind Alzheimer’s disease. Apolipoprotein E (ApoE) is a lipid transporting lipoprotein found within the brain and periphery. The APOE ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease and is a risk factor for VCID. Our lab has previously utilized a dietary model of hyperhomocysteinemia (HHcy) to induce VCID pathology and cognitive deficits in mice. This diet induces perivascular inflammation through cumulative oxidative damage leading to glial mediated inflammation and blood brain barrier breakdown. Here, we examine the impact of ApoE ε4 compared to ε3 alleles on the progression of VCID pathology and inflammation in our dietary model of HHcy. We report a significant resistance to HHcy induction in ε4 mice, accompanied by a number of related differences related to homocysteine (Hcy) metabolism and methylation cycle, or 1-C, metabolites. There were also significant differences in inflammatory profiles between ε3 and ε4 mice, as well as significant reduction in Serpina3n, a serine protease inhibitor associated with ApoE ε4, expression in ε4 HHcy mice relative to ε4 controls. Finally, we find evidence of pervasive sex differences within both genotypes in response to HHcy induction.

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“…Also in experimental TBI, high levels of expression of Serpina3n, an astroglial activation marker, are found in neurons in the early stage of the injury [ 9 ]. Meanwhile, it is observed in another study that the knockout of Serpina3n led to increased neuronal apoptosis in neurons, and that an MMP2-specific inhibitor might serve as a therapeutic target for neurotrauma [ 10 ]. In addition, Trem2 and Tyrobp have been identified as major regulators and therapeutic targets in TBI [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

The Gene Coexpression Analysis Identifies Functional Modules Dynamically Changed After Traumatic Brain Injury

Zhao

Wei

Zheng

et al. 2021

Computational and Mathematical Methods in Medicine

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Traumatic brain injury (TBI) is a major cause of morbidity and mortality, both in adult and pediatric populations. However, the dynamic changes of gene expression profiles following TBI have not been fully understood. In this study, we identified the differentially expressed genes (DEGs) following TBI. Remarkably, Serpina3n, Asf1b, Folr1, LOC100366216, Clec12a, Olr1, Timp1, Hspb1, Lcn2, and Spp1 were identified as the top 10 with the highest statistical significance. The weighted gene coexpression analysis (WGCNA) identified 12 functional modules from the DEGs, which showed specific expression patterns over time and were characterized by enrichment analysis. Specifically, the black and turquoise modules were mainly involved in energy metabolism and protein translation. The green yellow and yellow modules including Hmox1, Mif, Anxa2, Timp1, Gfap, Cd9, Gja1, Pdpn, and Gpx1 were related to response to wounding, indicating that expression of these genes such as Hmox1, Anxa2, and Timp1 could protect the brains from brain injury. The green yellow module highlighted genes involved in microglial cell activation such as Tyrobp, Cx3cr1, Grn, Trem2, C1qa, and Aif1, suggesting that these genes were responsible for the inflammatory response caused by TBI. The upregulation of these genes has been validated in an independent dataset. These results indicated that the key genes in microglia cell activation may serve as a promising therapeutic target for TBI. In summary, the present study provided a full view of the dynamic gene expression changes following TBI.

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SerpinA3N deficiency deteriorates impairments of learning and memory in mice following hippocampal stab injury

Cited by 24 publications

References 49 publications

Traumatic brain injury results in unique microglial and astrocyte transcriptomes enriched for type I interferon response

Traumatic brain injury results in unique microglial and astrocyte transcriptomes enriched for type I interferon response

Apolipoprotein E ε4/4 genotype limits response to dietary induction of hyperhomocysteinemia and resulting inflammatory signaling

The Gene Coexpression Analysis Identifies Functional Modules Dynamically Changed After Traumatic Brain Injury

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