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other·neurology, preclinical research, biomedical research, research methods·PMC10723838

A view of the genetic and proteomic profile of extracellular matrix molecules in aging and stroke

Frontiers in Cellular Neuroscience · 8 authors, 3 centres

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TL;DR

The central result is that after a stroke, aged brains show a shift towards increased matrix degradation and decreased protective matrix functions compared to young brains.

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The study performed a targeted re-analysis of existing RNA-Seq and proteomic data from young adult (3-month) and aged (18-month) female mice subjected to permanent middle cerebral artery occlusion (pMCAo) as a stroke model. The analysis focused on 56 genes related to the extracellular matrix (ECM). Key findings include a broad upregulation of genes for ECM-degrading enzymes (e.g., MMPs) and their regulators after stroke, with this upregulation enhanced in aged mice. Conversely, genes for protective ECM molecules (e.g., brevican) were downregulated, and this downregulation was more prominent in aged animals. The study concludes that aging shifts the balance in the brain from ECM protection toward degradation, potentially increasing vulnerability to ischemic injury. Limitations include the study being restricted to female mice and using specific time points for analysis.

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other

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neurology

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ORIGINAL PAPER

PMC10723838

A view of the genetic and proteomic profile of extracellular matrix molecules in aging and stroke

Frontiers in Cellular Neuroscience

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ABSTRACT

Abstract Introduction Modification of the extracellular matrix (ECM) is one of the major processes in the pathology of brain damage following an ischemic stroke. However, our understanding of how age-related ECM alterations may affect stroke pathophysiology and its outcome is still very limited. Methods We conducted an ECM-targeted re-analysis of our previously obtained RNA-Seq dataset of aging, ischemic stroke and their interactions in young adult (3-month-old) and aged (18-month-old) mice. The permanent middle cerebral artery occlusion (pMCAo) in rodents was used as a model of ischemic stroke. Altogether 56 genes of interest were chosen for this study. Results We identified an increased activation of the genes encoding proteins related to ECM degradation, such as matrix metalloproteinases (MMPs), proteases of a disintegrin and metalloproteinase with the thrombospondin motifs (ADAMTS) family and molecules that regulate their activity, tissue inhibitors of metalloproteinases (TIMPs). Moreover, significant upregulation was also detected in the mRNA of other ECM molecules, such as proteoglycans, syndecans and link proteins. Notably, we identified 8 genes where this upregulation was enhanced in aged mice in comparison with the young ones. Ischemia evoked a significant downregulation in only 6 of our genes of interest, including those encoding proteins associated with the protective function of ECM molecules (e.g., brevican, Hapln4, Sparcl1); downregulation in brevican was more prominent in aged mice. The study was expanded by proteome analysis, where we observed an ischemia-induced overexpression in three proteins, which are associated with neuroinflammation (fibronectin and vitronectin) and neurodegeneration (link protein Hapln2). In fibronectin and Hapln2, this overexpression was more pronounced in aged post-ischemic animals. Conclusion Based on these results, we can conclude that the ratio between the protecting and degrading mechanisms in the aged brain is shifted toward degradation and contributes to the aged tissues’ increased sensitivity to ischemic insults. Altogether, our data provide fresh perspectives on the processes underlying ischemic injury in the aging brain and serve as a freely accessible resource for upcoming research. Keywords: extracellular matrix, stroke, aging, genes, proteins

CITATION EXPORT

Martina Chmelova, Peter Androvic, Denisa Kirdajova et al.. A view of the genetic and proteomic profile of extracellular matrix molecules in aging and stroke. Frontiers in Cellular Neuroscience. (2023). https://doi.org/10.3389/fncel.2023.1296455

AUTHORS

8 · 3 CENTRES

Martina Chmelova, Peter Androvic, Denisa Kirdajova, Jana Tureckova, Jan Kriska, Lukas Valihrach, Miroslava Anderova, Lydia Vargova

1Department of Neuroscience, Second Faculty of Medicine, Charles University, Prague, Czechia
2Department of Cellular Neurophysiology, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czechia
3Laboratory of Gene Expression, Institute of Biotechnology of the Czech Academy of Sciences – BIOCEV, Vestec, Czechia