Mapping the transcriptomic changes of endothelial compartment in human hippocampus across aging and mild cognitive impairment

Abstract

Compromise of the vascular system has important consequences on cognitive abilities and neurodegeneration. The identification of the main molecular signatures present in the blood vessels of human hippocampus could provide the basis to understand and tackle these pathologies. As direct vascular experimentation in hippocampus is problematic, we achieved this information by computationally disaggregating publicly available whole microarrays data of human hippocampal homogenates. Three conditions were analyzed: ‘Young Adults’, ‘Aged’, and ‘aged with Mild Cognitive Impairment’ (MCI). The genes identified were contrasted against two independent data-sets. Here we show that the endothelial cells from the Younger Group appeared in an ‘activated stage’. In turn, in the Aged Group, the endothelial cells showed a significant loss of response to shear stress, changes in cell adhesion molecules, increased inflammation, brain-insulin resistance, lipidic alterations, and changes in the extracellular matrix. Some specific changes in the MCI group were also detected. Noticeably, in this study the features arisen from the Aged Group (high tortuosity, increased bifurcations, and smooth muscle proliferation), pose the need for further experimental verification to discern between the occurrence of arteriogenesis and/or vascular remodeling by capillary arterialization. This article has an associated First Person interview with the first author of the paper.

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

“…In addition, enhancement of ‘SMCs proliferation’ and ‘SMCs differentiation’ (FDR Eldered = 2.0 × 10 −10 vs. FDR Younger/MCI = 6.0 × 10 −5 ) accompanied these activities (see Figures 2a,b). Overall, these findings are in full agreement with previous reports focused on the analysis of ageing of the vascular compartment in the human hippocampus (Guebel et al, 2021).…”

“…This could seem contradictory with the evolution of the disease, but it is in line with several evidences: (1) Due to the geometry of the vectors representing the groups, the projections on the PC1 principal component actually shows what the compared groups have in common rather than their differences; (2) the vectors resulting from the same type of analysis but performed with endothelial cells showed a similar relationship (see Figure S1a); (3) only a few patterns (3 out of 12) appeared specifically associated to MCI changes (see Figure 2b,e,h). This is in line with what was observed when analysing hippocampal endothelial cells, where 8 out of 10 patterns of change occurred during the transition from younger to ageing, and not at the MCI stage (Guebel et al, 2021); (4) the relative ‘similarity’ between the younger and the MCI groups is also supported by the finding that herein the ‘ageing’ category appeared as far more significant in the elder group than in the MCI group, even when both groups had similar age distributions (FDR Eldered = 7.4 × 10 −13 vs. FDR MCI = 2.7 × 10 −6 ).…”

“…In line with the observation in hippocampal vasculature (Guebel et al, 2021), we corroborated here that the major functional changes in the hippocampal astrocytes actually operated during ageing and then subsidiarily in the MCI (Sections 3.1 and 3.2). The comparative analyses between younger, eldered and MCI groups allowed to stablish their astrocytic profiles, showing how the inputs (stimuli received) and the outputs (astrocytic responses, products generated) changed along the successive transitions (Section 3.3).…”

“…As is depicted in Figure 1, the optimized post‐processing method Q‐GDEMAR (Quantile‐Gaussian Deconvolution of Microarrays) (Guebel et al, 2016; Guebel & Torres, 2021) was the first step for the determination of the total differential genes in each group. The Q‐GDEMAR method has been validated and used with several working systems (Guebel et al, 2021; Guebel & Torres, 2016, 2018). Thereafter, a double filtering procedure was additionally applied.…”

“…In this regard, a strategy based on ‘computational dissections’ of data from brain tissue samples was previously developed. This approach makes it possible to systematize and clarify several aspects associated to the problem of vasculature in the human hippocampus under in vivo conditions, an information difficult to obtain experimentally (Guebel et al, 2021). This virtual dissection pursued several objectives: (1) to reposition non‐specific information of microarrays from total homogenates of hippocampus, to specific information corresponding to hippocampal vasculature, and (2) to contrast the recovered information against several other sources originated in the application of RNA‐sequencing on endothelial cells.…”