Molecular fingerprints of aging human brain vasculature: Meta-analysis of single nucleus RNA sequencing data
Presentation by Philipp Arndt, Magdeburg
Time: 10:45–11:15
Dysfunction of the human brain vasculature contributes to several brain disorders including age-related cognitive decline and is therefore of great medical importance. Yet so far, there is no molecular map depicting the human brain microvasculature remodeling during aging.
Background: Dysfunction of the human brain vasculature contributes to several brain disorders including age-related cognitive decline and is therefore of great medical importance. Yet so far, there is no molecular map depicting the human brain microvasculature remodeling during aging.
Methods: Publicly available single nucleus RNA sequencing data from cognitively unimpaired individuals were used to extract data on the aging of major vascular cell types in the brain and investigate underlying molecular mechanisms. Seurat was used for data preprocessing, MAST, a single-cell-based method, for the identification of aging-associated differently expressed genes (DEG, false discovery ratio < 0.05, fold change > 10%), and Enrichr for identification of gene ontology (GO) biological processes (p < 0.01).
Results: Based on five suitable studies, we extracted 107,862 vascular cells (52% endothelial cells, 31% pericytes, 13% fibroblasts, 4% smooth muscle cells (SMCs)) from 253 individuals, aged 51 to 108 years. Comparing individuals in midlife aged 51 - 60 years, with old individuals, aged >80 years, most DEGs were found in fibroblasts (220 upregulated, 105 downregulated), followed by pericytes (187 upregulated, 109 downregulated), SMCs (143 upregulated, 75 downregulated) and endothelial cells (130 upregulated, 83 downregulated). Among the most upregulated genes in all four cell types was ADAMTS9 that encodes a protease digesting ECM proteoglycans and has a protease-independent function in promoting the transport from the endoplasmic reticulum to the Golgi apparatus of a variety of secretory cargos. GO-term analysis revealed that upregulated genes in aging were associated with extracellular matrix organization and receptor protein tyrosine kinase signaling in pericytes, SMCs and fibroblasts, response to cytokines in endothelial cells, pericytes and fibroblasts, transport across the blood-brain-barrier in pericytes and fibroblasts and import of nutrients in endothelial cells. Downregulated genes were associated with cellular response to heat in endothelial cells, SMCs and fibroblasts, ATP metabolic process in SMCs and fibroblasts and response to unfolded protein in endothelial cells and SMCs.
Conclusions: Aging in brain vascular cells interferes with diverse cellular functions and leads to vascular extracellular matrix remodeling.