Aging‐induced dysregulation of Dicer1‐dependent microRNA expression impairs angiogenic capacity of rat cerebromicrovascular endothelial cells

Tucsek, Zsuzsanna; Sоsnowska, Danuta; Tóth, Peter P.; Gautam, Tripti; Valcarcel-Ares, Noa M.; Sonntag, William E.; Ungvári, Zoltán

doi:10.1096/fasebj.27.1_supplement.688.7

Cited by 6 publications

(6 citation statements)

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“…6d ). The stability of Dicer which is critical to miRNA expression in the brain [83, 84, 103, 104] is sensitive to ROS and interferons (IFNs) [105, 106] and most of its expression in the brain is lost during aging [85]. During AD Aβ plaques cause further upregulation of ROS and induce inflammation resulting in elevated IFNs ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Death Induced by Survival gene Elimination (DISE) is correlated with neurotoxicity in Alzheimer’s disease and aging

Paudel

Jeong

Martinez

et al. 2022

Preprint

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Background: Alzheimer's disease (AD) is characterized by progressive neurodegeneration, but the specific events that cause cell death remain poorly understood. Death Induced by Survival gene Elimination (DISE) is a recently discovered powerful cell death mechanism mediated by short (s) RNAs including micro (mi) RNAs acting through the RNA induced silencing complex (RISC). G-rich 6mer seed sequences in the sRNAs (position 2-7) target hundreds of C-rich seed matches in genes essential for cell survival resulting in the simultaneous activation of multiple cell death pathways. The RISC of most cells is occupied by miRNAs with nontoxic 6mer seeds, which may protect them from DISE by blocking loading of toxic sRNAs. However, during aging when miRNA expression decreases, toxic sRNAs may enter the RISC more readily leaving cells primed for DISE. Whether DISE contributes to neuronal loss in a neurodegenerative disease such as AD has not been evaluated. Methods: Using Ago precipitation and RNAseq (Ago-RP-Seq) combined with SPOROS, a recently developed bioinformatics pipeline to analyze small RNAseq data with respect to 6mer seed toxicity, we analyzed RISC bound sRNAs (R-sRNAs) in in vitro models and in the brains of multiple in vivo AD mouse models, aged mice, and AD patients. Results: We find that in in vitro cell line studies, in mouse models that show neurodegeneration, and in the aging brain R-sRNAs shift to more toxic seeds. In contrast, in cells that survived in post-mortem brains of AD patients and the brains of "SuperAgers", individuals over age 80 who have superior memory performance, R-sRNAs shift to more nontoxic seeds, supporting a protective function of miRNAs. Conclusion: Our data provide first evidence of a contribution of DISE to the neurotoxicity seen in AD suggesting that increasing the levels of protective miRNAs in the brain or blocking the activity of toxic R-sRNAs could lead to a novel way of treating the disease.

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Section: Discussionmentioning

confidence: 99%

Death Induced by Survival gene Elimination (DISE) is correlated with neurotoxicity in Alzheimer’s disease and aging

Paudel

Jeong

Martinez

et al. 2022

Preprint

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“…One explanation for this finding may be due to an overall reduction in protein translation among the late passage, senescent cells, or dysfunctional translational "machinery." Recent studies have shown that global protein translation is reduced among senescent cells, and Dicer expression and activity is likewise dysfunctional (58)(59)(60). Glucose stress may accelerate or enhance this age-associated protein translation dysfunction.…”

Section: Glucose Stress Induces Transcriptional Dysregulation Of Nosmentioning

confidence: 99%

Exposure to High or Low Glucose Levels Accelerates the Appearance of Markers of Endothelial Cell Senescence and Induces Dysregulation of Nitric Oxide Synthase

Rogers

Zhang

Azhar

et al. 2013

The Journals of Gerontology: Series A

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To test the hypothesis that aging impairs endothelial cell response to glucose stress, we utilized a human umbilical vein endothelial cell in vitro model in which clinically relevant concentrations of normal (5.5 mM), high (25 mM), and low (1.5mM) glucose were tested. With advancing population doubling, exposure to normal glucose gradually decreased endothelial nitric oxide synthase expression and activity, resulting in slow, progressive development of markers of cell senescence (by population doubling level [PDL] 44). High or low glucose treatment accelerated the appearance of markers of senescence (by ~PDL 35) along with declines in endothelial nitric oxide synthase expression and activity. Human umbilical vein endothelial cells exposed to alternating low and high glucose gave even more rapid acceleration in the appearance of markers of senescence (by ~PDL 18) and reduction in endothelial nitric oxide synthase levels. Thus, exposure to low and high glucose induces earlier appearance of markers of endothelial cell senescence and dysregulation of the nitric oxide synthase gene and protein expression and function. These findings will help to elucidate endothelial dysfunction associated with glucose intolerance and improve future therapy for diabetic seniors.

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“…Since the p53 signaling pathway is among the top pathways highlighted by our Gene Ontology analysis (Table 2), p53 could be responsible for the global downregulation of miRNAs through a negative feedback loop mechanism. In a previous study, exogenous H 2 O 2 exposure has been shown to cause a significant decrease in Dicer expression resulting in the downregulation of 89% of microRNAs that are normally expressed in endothelial cells (Ungvari et al, 2013).…”

Section: Discussionmentioning

confidence: 98%

Identification of microRNA-mRNA regulatory network associated with oxidative DNA damage in human astrocytes

et al. 2022

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The high lipid content of the brain, coupled with its heavy oxygen dependence and relatively weak antioxidant system, makes it highly susceptible to oxidative DNA damage that contributes to neurodegeneration. This study is aimed at identifying specific ROS-responsive miRNAs that modulate the expression and activity of the DNA repair proteins in human astrocytes, which could serve as potential biomarkers and lead to the development of targeted therapeutic strategies for neurological diseases. Oxidative DNA damage was established after treatment of human astrocytes with 10μM sodium dichromate for 16 h. Comet assay analysis indicated a significant increase in oxidized guanine lesions. RT-qPCR and ELISA assays confirmed that sodium dichromate reduced the mRNA and protein expression levels of the human base-excision repair enzyme, 8-deoxyguanosine DNA glycosylase 1 (hOGG1). Small RNAseq data were generated on an Ion Torrent™ system and the differentially expressed miRNAs were identified using Partek Flow® software. The biologically significant miRNAs were selected using miRNet 2.0. Oxidative-stress-induced DNA damage was associated with a significant decrease in miRNA expression: 231 downregulated miRNAs and 2 upregulated miRNAs (p < 0.05; >2-fold). In addition to identifying multiple miRNA-mRNA pairs involved in DNA repair processes, this study uncovered a novel miRNA-mRNA pair interaction: miR-1248:OGG1. Inhibition of miR-1248 via the transfection of its inhibitor restored the expression levels of hOGG1. Therefore, targeting the identified microRNA candidates could ameliorate the nuclear DNA damage caused by the brain’s exposure to mutagens, reduce the incidence and improve the treatment of cancer and neurodegenerative disorders.

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Aging‐induced dysregulation of Dicer1‐dependent microRNA expression impairs angiogenic capacity of rat cerebromicrovascular endothelial cells

Cited by 6 publications

References 0 publications

Death Induced by Survival gene Elimination (DISE) is correlated with neurotoxicity in Alzheimer’s disease and aging

Death Induced by Survival gene Elimination (DISE) is correlated with neurotoxicity in Alzheimer’s disease and aging

Exposure to High or Low Glucose Levels Accelerates the Appearance of Markers of Endothelial Cell Senescence and Induces Dysregulation of Nitric Oxide Synthase

Identification of microRNA-mRNA regulatory network associated with oxidative DNA damage in human astrocytes

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