Systematic Review of glucose transporter alterations in human Alzheimer’s disease and rodent Alzheimer’s disease models

The brain requires a constant glucose supply to fuel energy production for numerous cellular functions. Glucose is transported into the brain by means of specialized glucose transporter proteins (GLUTs), which ensure transport across the blood-brain barrier (BBB) and uptake in neurons and glia. Dysregulation of brain glucose metabolism has been implicated in contributing to neurodegenerative diseases, including Alzheimer's Disease (AD). While development of neuronal amyloid-beta plaques and tau-containing tangles both occur in AD, recent research suggests that metabolic changes, including GLUT alterations, could play a crucial role in disease progression. This review investigates alterations in GLUT expression occurring in AD patients and related rodent models of AD. Reduction of GLUT1 and GLUT3, key transporters for glucose transport across the BBB and cellular uptake in the brain, was consistently observed in AD patients. These alterations were associated with AD pathology and cognitive decline in several studies. While most rodent studies replicate the findings in human AD, others discern diverse results, highlighting the complexity of AD modeling in laboratory animals. This was further supported by our own original data showing divergent GLUT1 mRNA and protein alterations in Tg-SwDI and 5xFAD mice. GLUT2 and GLUT4 have been less studied, but studies in AD patients suggest an increase in GLUT2 expression, whereas a possible correlation between AD and GLUT4 is absent. Results from studies of GLUT2 and GLUT4 expression in rodent models of AD were too inconsistent to make any clear conclusions. Contributing to the complexity of GLUT's role in AD pathophysiology, rodent studies suggest that GLUT1 deficiency not only contributes to but also exacerbates AD progression by further restricting glucose transport to the brain, leading to intensified metabolic impairments. Together, these findings support that restoring the expression of GLUTs denotes a potential therapeutic target for limiting disease progression in AD. However, due to the divergent results across various studies, it is challenging to draw definitive conclusions regarding GLUT expression in rodent AD models. Some models may not fully replicate the GLUT and metabolic changes observed in AD, posing a limitation that is crucial to consider in future studies to enhance their translational potential.