Aquaporin-4 Mislocalization and Glucose Hypometabolism in Alzheimer's Disease

Project Summary

Reduced entry of glucose into the brain from the blood is thought to play a major role in Alzheimer’s disease (AD). Our research aims to understand why this happens and to determine whether it’s possible to reduce damage to the brain by preventing the reduction in energy use that results from reduced glucose supply. We are specifically studying the role of aquaporin-4 (AQP4), a protein that is heavily enriched at the interface between blood vessels and the brain, in regulating the rate of glucose transport into the brain. In AD the amount of AQP4 surrounding blood vessels is reduced and so one of the goals of the research is to determine if reduced AQP4 by itself can account for the decreased glucose uptake observed in Alzheimer’s patients.

Genetic deletion of AQP4 causes increased amyloid deposition in the brain of Alzheimer’s model mice. We are therefore also performing experiments to determine if this can be prevented by dietary changes that reduce glucose requirements of the brain. Additional experiments will use advanced optical imaging approaches to study the structural reorganizations that lead to loss of AQP4 from the area around vessels. Results of these experiments will help design strategies that prevent these structural changes, that could reverse the defective glucose uptake and reduce pathology in the Alzheimer’s brain.

Our work introduces a novel conceptual framework for understanding how activity-dependent glucose uptake into the brain is regulated and how uptake fails in AD. In addition to the conceptual novelty, innovative technical approaches are used to study alterations in the spatial relationships between proteins that surround blood vessels in the brain. These include super-resolution optical imaging that allows visualization of protein organization with unprecedented clarity.  

Completion of this study will result in an improved understanding of why glucose uptake is reduced in the AD brain, which will facilitate the identification of novel targets for Alzheimer’s drug development. Some studies have suggested that dietary modifications aimed at reducing the brain’s demand for glucose can help preserve cognitive function in AD patients, and our study will help to clarify when dietary modification is appropriate for AD patients.