Influence of sex, age and diabetes on brain transcriptome and proteome modifications following cerebral ischemia

Ramiro L, Faura J, Simats A et al. BMC Neurosci. 2023 Jan 27;24(1):7. doi: 10.1186/s12868-023-00775-7. PMID: 36707762

Abstract: Ischemic stroke is a major cause of death and disability worldwide. Translation into the clinical setting of neuropro‑ tective agents showing promising results in pre-clinical studies has systematically failed. One possible explanation is that the animal models used to test neuroprotectants do not properly represent the population afected by stroke, as most of the pre-clinical studies are performed in healthy young male mice. Therefore, we aimed to determine if the response to cerebral ischemia difered depending on age, sex and the presence of comorbidities. Thus, we explored proteomic and transcriptomic changes triggered during the hyperacute phase of cerebral ischemia (by transient intraluminal middle cerebral artery occlusion) in the brain of: (1) young male mice, (2) young female mice, (3) aged male mice and (4) diabetic young male mice. Moreover, we compared each group’s proteomic and transcriptomic changes using an integrative enrichment pathways analysis to disclose key common and exclusive altered proteins,
genes and pathways in the frst stages of the disease. We found 61 diferentially expressed genes (DEG) in male mice, 77 in females, 699 in diabetics and 24 in aged mice. Of these, only 14 were commonly dysregulated in all groups. The enrichment pathways analysis revealed that the infammatory response was the biological process with more DEG in all groups, followed by hemopoiesis. Our fndings indicate that the response to cerebral ischemia regarding prot‑ eomic and transcriptomic changes difers depending on sex, age and comorbidities, highlighting the importance of incorporating animals with diferent phenotypes in future stroke research studies.

Funding: This work has been funded by Instituto de Salud Carlos III (PI18/00804) and by the European Regional Development Fund (FEDER). Neurovascular Research Laboratory takes part in the Spanish stroke research network RICORS-ICTUS. L.R is supported by a pre-doctoral fellowship from the Instituto de Salud Carlos III (IFI17/00012)

Protein content of blood-derived extracellular vesicles: An approach to the pathophysiology of cerebral hemorrhage

Laso-García F, Piniella D, Gómez-de Frutos MC et al.  Front Cell Neurosci. 2023 Jan 19;16:1058546. doi: 10.3389/fncel.2022.1058546. eCollection 2022. PMID: 36776230


Introduction: Extracellular vesicles (EVs) participate in cell-to-cell paracrine signaling and can be biomarkers of the pathophysiological processes underlying disease. In intracerebral hemorrhage, the study of the number and molecular content of circulating EVs may help elucidate the biological mechanisms involved in damage and repair, contributing valuable information to the identification of new therapeutic targets.
Methods: The objective of this study was to describe the number and protein content of blood-derived EVs following an intracerebral hemorrhage (ICH). For this purpose, an experimental ICH was induced in the striatum of Sprague-Dawley rats and EVs were isolated and characterized from blood at baseline, 24 h and 28 days. The protein content in the EVs was analyzed by mass spectrometric data-dependent acquisition; protein quantification was obtained by sequential window acquisition of all theoretical mass spectra data and compared at pre-defined time points.
Results: Although no differences were found in the number of EVs, the proteomic study revealed that proteins related to the response to cellular damage such as deubiquitination, regulation of MAP kinase activity (UCHL1) and signal transduction (NDGR3), were up-expressed at 24 h compared to baseline; and that at 28 days, the protein expression profile was characterized by a higher content of the proteins involved in healing and repair processes such as cytoskeleton organization and response to growth factors (COR1B) and the regulation of autophagy (PI42B).
Discussion: The protein content of circulating EVs at different time points following an ICH may reflect evolutionary changes in the pathophysiology of the disease.

Funding: This work was supported by the Spanish Ministry of HealthCarlos III Health Institute (ISCIII) and the European Regional Development Fund (FEDER Funding) under grant PI17/01922 and PI20/00243, the Invictus Plus network under grant RD16/0019/0005, RICORS network under grant RD21/0006/0012, Miguel Servet under grant CPII20/00002 to MG-F; CP20/00024 to LO-O, Sara Borrell under grant CD19/00033 to MP-M, Ministerio de Universidades, Plan de Recuperación, Transformación y Resiliencia, Universidad Autónoma de Madrid under grant CA1/RSUE/2021-00753 to DP, and the Spanish Ministry of Health-Carlos III Health Institute (ISCIII) under grant FI18/00026 to FL-G, FI17/00188 to MG-F