Mathematical modelling of brain mTOR activity identifies selective vulnerability of cell types and signalling pathways

The mTOR pathway is a global regulator of protein biosynthesis and cellular homeostasis. Understanding the differences in mTOR pathway activity between cell types is important for elucidating the role of mTOR in physiological and pathophysiological processes. The non-linear structure of the pathway, with multiple feedback loops and inputs complicates the interpretation of experimental data and requires mathematical modelling. We modelled mTOR activation under healthy and disease conditions using recently published single nuclei gene expression data from the human brain. The model predicts substantial variations in mTOR pathway activity between cell types, with neurons and astrocytes being highly sensitive to insulin and neuregulins, while vascular smooth muscle cells and pericytes are highly sensitive to PDGF. Two principal negative regulators of mTOR - TSC and PTEN have prominent roles in PDGF-mediated mTOR activation in endothelial cells and oligodendrocytes. In Alzheimer’s Disease brain we find that insulin-mediated activitation of mTOR pathway is selectively upregulated in microglia and oligodendrocytes and downregulated in other cells. Our mathematical modelling characterises ligand sensitivity of cerebrovascular cell types and provides insights into the brain mTOR dynamics in health and disease.