Compromised function of a glial glucose transporter in aging and Alzheimer's disease

SUMMARY Aging is the most powerful risk factor for Alzheimer’s disease (AD), and it contributes to the odds of type-2 diabetes mellitus (T2D) as well. Aging is also 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. This idea will be tested through studies of the status and function of glucose transport proteins in aging mouse and human brains, along with comparisons between normal aging, AD, and T2D. Through genetic modification of mice, we will modulate the levels of the most important astrocytic glucose transporter to determine if it is i) sufficient to bring about interrupted glucose delivery and memory deficits, and ii) necessary for the presentation of these problems in an AD model. These studies thus explore a novel hypothesis about a specific element of energy utilization in the aging brain and its connection to age-related cognitive impairment. As such, the project may provide innovative strategies for therapeutic intervention.