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

Abstract

Ischemic stroke is a major cause of death and disability worldwide. Translation into the clinical setting of neuroprotective 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 affected 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 differed 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 first stages of the disease. We found 61 differentially 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 inflammatory response was the biological process with more DEG in all groups, followed by hemopoiesis. Our findings indicate that the response to cerebral ischemia regarding proteomic and transcriptomic changes differs depending on sex, age and comorbidities, highlighting the importance of incorporating animals with different phenotypes in future stroke research studies.

Selective deletion of interleukin-1 alpha in microglia does not modify acute outcome but regulates neurorepair processes after experimental ischemic stroke

“…GJB2 encodes for a gap junction protein known as Connexin 26, present in astrocytes and leptomeningial cells in the brain [27]. NPAS4 encodes for a transcription factor whose expression is induced in upon cerebral ischemia, which has been associated with a neuroprotective role, potentially through modulation of cell death and inflammatory responses [28]. Importantly, canonical pathways analysis identified the neuronal CREB signaling pathway as the most down-regulated in the absence of microglial IL-1α expression.…”

Neuroinflammation and Brain Disease

“…For example, TBI can negatively impact various organs, including the pulmonary, gastrointestinal, cardiovascular, renal, and immune systems [ 21 ]. Furthermore, it should also be considered that sex, age and comorbidities can strongly influence inflammatory responses in acute and chronic neurodegeneration ( 22 – 23 ). Finally, to translate results from bench to bedside, consistent improvement and application of diagnostic and prognostic tools, including functional neuroimaging, advanced magnetic resonance imaging processing and meaningful biomarkers [ 24 ] to characterize the timing, localization, extent, and duration of inflammation are clearly important.…”