The availability of glucose in the central nervous system is essential for neuronal function, and brain glucose levels have been shown to regulate neuronal activity. The regulation of glucose supply from the bloodstream to and within the brain is controlled through the glucose transporter GLUT1, which is highly expressed in astrocytes.
Although glucose regulation in the brain has traditionally been considered an insulin-independent process, there is ongoing debate regarding the role of insulin action in the control of brain glucose metabolism. However, the molecular mechanisms and the key cellular mediators that govern the central actions of insulin remain far from being fully understood. In fact, to date, the possibility that insulin signaling in astrocytes plays a functional role in cerebral glucose uptake and its impact on Alzheimer's disease (AD) has never been investigated.
Preliminary data obtained by our group have demonstrated that the ablation of GLUT1 in astrocytes promotes the overexpression of the insulin receptor (IR). These findings indicate that insulin signaling and astrocyte-mediated glucose uptake may be closely interconnected. Therefore, the central objective of the present project is to evaluate whether reductions in IR levels in astrocytes can induce alterations in GLUT1 expression and consequently cause changes in glucose uptake, modulate astrocyte-neuron communication, and ultimately reprogram neuronal activity, thereby inducing detrimental effects in AD.
The completion of this project will provide a better understanding of the fundamental mechanisms underlying AD pathology and will open new avenues for clinical research aimed at improving the prevention of neurodegenerative diseases, promoting health, and developing novel therapeutic strategies.