Aquaporin-4 Mislocalization and Glucose Hypometabolism in Alzheimer's Disease
The healthy brain consumes large amounts of energy, ten times as much as other similarly sized regions of the body, but in Alzheimer’s disease (AD), the supply of energy-rich sugar from the blood to brain is reduced; it is not known why this happens. Blood vessels in the brain are surrounded by cells that contain a very large amount of a protein called aquaporin-4 that we think is involved in regulating how tightly these cells surround the vessels. In AD the amount of aquaporin-4 around vessels is reduced and we believe this causes the cells to swell around the vessels, blocking sugar from getting into the brain. We propose to do experiments that will test this idea and consider new therapies to remove the block for sugar transport into the brain.
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.
About the Researcher
After an undergraduate degree at the University of Cambridge, UK, I left to pursue my career in the USA with a PhD in cellular immunology at the University of New Mexico. During the course of my PhD work, I became deeply interested in advanced fluorescent imaging techniques, particularly the emerging technologies of physiological imaging with ion indicators and fluorescent proteins. These interests led me to a postdoc in the laboratory of Professor Milton Charlton at the University of Toronto, where I learned how to study release and recycling of synaptic vesicles in cultured mammalian neurons with optical and electrophysiological methods. After completion of my postdoc I joined Professor Alan Verkman’s research group at the University of California, San Francisco, and continued to develop imaging methods for studying membrane organization in astrocytes and its relation to fluid transport in the brain. Our work has led us to question existing ideas on the role astrocytes play in clearance of toxic protein aggregates in Alzheimer’s disease. We are currently studying how alterations in the membrane composition of astrocyte foot processes in Alzheimer’s affects solute transport across the blood-brain barrier.
Alzheimer’s disease (AD) is one of the most challenging problems facing the current generation of biomedical researchers. My hope is that detailed observation of pathophysiological processes in model mice and human samples will lead us to an improved understanding of how deposition of amyloid plaques in the brain leads to neurodegeneration. With understanding of how neurodegeneration occurs, new therapeutic approaches will become apparent. The support provided by BrightFocus will allow us to apply next-generation optical imaging techniques to study the development of pathology in AD. I am extremely grateful to the BrightFocus donors for the opportunity to continue working in this most challenging and rewarding of areas.
First published on: July 18, 2018
Last modified on: May 30, 2019