Abstract
The molecular signatures of cells in the brain have been revealed in unprecedented detail, yet the ageing-associated genome-wide expression changes that may contribute to neurovascular dysfunction in neurodegenerative diseases remain elusive. Here, we report zonation-dependent transcriptomic changes in aged mouse brain endothelial cells (ECs), which prominently implicate altered immune/cytokine signaling in ECs of all vascular segments, and functional changes impacting the blood–brain barrier (BBB) and glucose/energy metabolism especially in capillary ECs (capECs). An overrepresentation of Alzheimer disease (AD) GWAS genes is evident among the human orthologs of the differentially expressed genes of aged capECs, while comparative analysis revealed a subset of concordantly downregulated, functionally important genes in human AD brains. Treatment with exenatide, a glucagon-like peptide-1 receptor agonist, strongly reverses aged mouse brain EC transcriptomic changes and BBB leakage, with associated attenuation of microglial priming. We thus revealed transcriptomic alterations underlying brain EC ageing that are complex yet pharmacologically reversible.
Highlights
1234567890():,; The molecular signatures of cells in the brain have been revealed in unprecedented detail, yet the ageing-associated genome-wide expression changes that may contribute to neurovascular dysfunction in neurodegenerative diseases remain elusive
We found that respiratory electron transport chain/ATP synthesis, and glucose/energy metabolism (e.g. Hmgcs[2], Pea15a, and multiple SLC transporter genes) associated genes were most enriched in the downregulated differentially expressed genes (DEGs) of aged capillary ECs (capECs), and to a lesser extent in aEC1 and vcapEC (Fig. 2a, b)
Advances in single-cell transcriptomic profiling have led to the introduction of the vascular zonation concept, which enables the fine classification of endothelial cells (ECs) subtypes along the arteriovenous axis based on gene expression differences, highlighting their potential functional distinctions[13]
Summary
1234567890():,; The molecular signatures of cells in the brain have been revealed in unprecedented detail, yet the ageing-associated genome-wide expression changes that may contribute to neurovascular dysfunction in neurodegenerative diseases remain elusive. Complex cellular and functional changes occur in the brain These include neurovascular dysfunction manifesting in blood–brain barrier (BBB) breakdown associated with microscopic pathological changes of vascular cells[1,2]. GLP-1R is expressed by multiple cell types including microglia and subsets of neurons[28,40,41], while peripherally it has been reported to be expressed by subsets of vascular and immune cells[38,39] It remains to be tested whether GLP-1R agonists may act partly via reversal of neurovascular ageing, accounting for the general applicability as potential therapeutics for multiple neurodegenerative conditions
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