Human hippocampal astrocytes: Computational dissection of their transcriptome, sexual differences and exosomes across ageing and mild‐cognitive impairment

Abstract

AbstractThe role of astrocytes in Alzheimer's disease is often disregarded. Hence, characterization of astrocytes along their early evolution toward Alzheimer would be greatly beneficial. However, due to their exquisite responsiveness, in vivo studies are difficult. So public microarray data of hippocampal homogenates from (healthy) young, (healthy) elder and elder with mild cognitive impairment (MCI) were subjected to re‐analysis by a multi‐step computational pipeline. Ontologies and pathway analyses were compared after determining the differential genes that, belonging to astrocytes, have splice forms. Likewise, the subset of molecules exportable to exosomes was also determined. The results showed that astrocyte's phenotypes changed significantly. While already ‘activated’ astrocytes were found in the younger group, major changes occurred during ageing (increased vascular remodelling and response to mechanical stimulus, diminished long‐term potentiation and increased long‐term depression). MCI's astrocytes showed some ‘rejuvenated’ features, but their sensitivity to shear stress was markedly lost. Importantly, most of the changes showed to be sex biassed. Men's astrocytes are enriched in a type ‘endfeet‐astrocytome’, whereas women's astrocytes appear close to the ‘scar‐forming’ type (prone to endothelial dysfunction, hypercholesterolemia, loss of glutamatergic synapses, Ca+2 dysregulation, hypoxia, oxidative stress and ‘pro‐coagulant’ phenotype). In conclusion, the computational dissection of the networks based on the hippocampal gene isoforms provides a relevant proxy to in vivo astrocytes, also revealing the occurrence of sexual differences. Analyses of the astrocytic exosomes did not provide an acceptable approximation to the overall functioning of astrocytes in the hippocampus, probably due to the selective cellular mechanisms which charge the cargo molecules.