Role of glucose transport in Alzheimer's disease pathogenesis

Alzheimer’s disease (AD) is associated with a decline in the brain’s use of glucose, its most important fuel. Astrocytes play a key role in shuttling glucose from the bloodstream to where it is needed by the neuronal units of activity deeper in the brain tissue. We find evidence of a defect in a key glucose transport molecule of astrocytes in AD and in a mouse line genetically modified to reproduce some aspects of AD. This mouse line, overproducing the β-amyloid peptide (Aβ), exhibits dysregulation of circulating glucose, as well as a decline in brain glucose use. These effects are correlated with poor performance in a test of spatial memory. Further mimicking human AD, the mice show these problems in the absence of obesity, hyperglycemia, disruption of appetite, changes in physical activity, pancreatic abnormality, or insulin resistance. Together, these findings inspire the hypothesis that Aβ, the levels of which begin to rise in the aging brain even without frank AD, perturbs the ability of astrocytes to bring peripheral glucose to neurons, where it is needed for the increased neurological activity associated with memory and other functions. We further propose that the product of a genetic variant of the apolipoprotein E gene known as ApoE4 contributes to the glucose deficiency, likely through its impact on gene regulation. These ideas will be tested through studies of the status and function of glucose transport proteins in the mouse model of AD. First, we will assess the relative roles of astrocytes and other cell types and inflammation in these events. We will also determine the role of ApoE, particularly that of ApoE4’s interaction with specific DNA regulatory elements, in the disruption of glucose transport. Finally, we will utilize on-campus drug-discovery resources in an attempt to reverse the glucose dysregulation pharmacologically. These studies test a novel hypothesis about a specific element of energy utilization in the AD brain and its connection to cognitive impairment. As such, the project may provide innovative strategies for therapeutic intervention. Relevance This project focuses on the impact made on brain energy utilization by risk factors for Alzheimer’s such as inflammation and apolipoprotien E4. Alzheimer’s involves a drop in brain glucose delivery. This study will help us understand details about how Alzheimer risk factors bring about mental deterioration, and it may identify chemical compounds that can be developed into therapeutic agents.