Cerebral blood vessels are composed of endothelial cells that interact closely with astrocytes, regulating the transport of nutrients such as glucose into the brain. Glucose supply from the bloodstream to the brain is mainly controlled by the glucose transporter GLUT1. GLUT1 is highly expressed in both endothelial cells and astrocytes, although its expression is more abundant in astrocytes. Due to their strategic location at the interface between blood vessels and neurons, astrocytes are ideally positioned to regulate cerebral glucose uptake.
The preclinical stage of Alzheimer’s disease (AD) is characterized by reduced glucose consumption in the brain. However, the contribution of glial cells to this impaired glucose uptake remains unclear. Alterations in GLUT1 expression at the blood-brain barrier (BBB) endothelium have been associated with the development of AD through the promotion of neurovascular dysfunction. Although these findings are compelling, it remains uncertain whether disease progression is driven by reduced glucose uptake itself or by BBB disruption. Therefore, the main objective of this project is to determine whether reduced GLUT1 levels specifically in astrocytes contribute to Alzheimer-like neurodegeneration independently of cerebrovascular alterations.
To address this question, tamoxifen-inducible Cre/loxP mouse models will be used to selectively delete GLUT1 in astrocytes in adult mice. To evaluate whether astrocytic GLUT1 deficiency contributes to AD progression, these mice will be crossed with the APP/PS1 transgenic mouse model of Alzheimer’s disease.
In addition, previous work by the principal investigator demonstrated that high-fat diets suppress GLUT1 expression in cerebral endothelial cells, leading to reduced brain glucose levels and memory impairment. Both effects were restored through a compensatory response mediated by VEGF. In this context, the second objective of the project is to investigate whether exogenous VEGF administration can rescue cognitive deficits in AD mice lacking astrocytic GLUT1.
Given the growing evidence linking GLUT1 dysfunction to Alzheimer’s disease, astrocytic glucose transport capacity may represent a key factor in the pathogenesis of neurodegeneration. This project aims to provide a deeper understanding of the mechanisms underlying AD while also identifying new therapeutic opportunities. Furthermore, the findings may improve the identification and validation of an important early risk factor for AD — reduced cerebral glucose uptake during the initial stages of the disease — enabling better diagnostic tools, preventive strategies, and early interventions through VEGF-based therapies.
Overall, the data generated from this project will be essential to clarify the role of astrocytic GLUT1 in the onset and progression of Alzheimer’s disease, and evaluate the therapeutic potential of VEGF to restore glucose uptake and potentially treat AD.
Collectively, the proposed experiments support the development of innovative approaches aimed at improving the quality of life of patients suffering from Alzheimer’s disease.