Tokyo, Japan – Researchers from Tokyo Metropolitan University have discovered that impaired glucose metabolism in glial cells, a type of cell in our nervous system, plays a key role in the degeneration caused by Alzheimer's disease. Using fruit fly retinas, they showed that promoting glucose metabolism in glial cells with tau protein build-up, like in Alzheimer's patients, helps relieve inflammation and photoreceptor degeneration. Their findings present an exciting new therapeutic target for treating neurodegenerative conditions.
Alzheimer's disease (AD) is the world's leading cause of dementia among older people and continues to have a devastating impact on people's quality of life. Scientists are working against the clock to unravel the vast network of mechanisms by which AD affects our nervous system. We know, for example, that AD is characterized by a build-up of tau protein inside cells, but the ways in which this leads to neurodegeneration are not yet fully understood.
A team led by Professor Kanae Ando of Tokyo Metropolitan University have turned their attention to how tau protein build-up affects glial cells, non-neuronal cells in our central nervous system that help support, feed, and protect neurons. Importantly, the ways in which glial cells work have a lot do with what happens in AD patients. For example, glial cells are known to clear away abnormal build-up of protein, accompanied by an inflammatory response; neuroinflammation is a core pathology of AD. They play an important role in helping neurons stay fueled by metabolizing glucose; a drastic drop in brain glucose metabolism is another feature of AD patients. However, the relationship between changes to glial cell glucose metabolism and tau protein build-up was not known.
Using Drosophila fruit flies as a model, firstly the team showed that flies modified to have a tau-protein build-up in the retina showed neurodegeneration, swelling in nearby regions, and the formation of abnormal inclusions. They were able to show that the latter of these was caused by glial cells being abnormally active. To explore how this related to its glucose metabolism, they were able to use genetic modification techniques to express more of a glucose transporting protein (GLUT) in glial cells. Amazingly, this led to suppression of neurodegeneration and less inflammation, even though it did not lead to changes to tau protein build-up. This shows that tau-protein build-up causes glial cells to suffer from a significant drop in glucose metabolism.
The team propose that glial glucose metabolism might be a new target for novel therapies for neurodegenerative conditions. Diseases like Parkinson's, for example, are also characterized by neuroinflammation. Any advances which might cure, prevent, or even slow down the onset of any of these conditions promise to have a game-changing impact on human society.
This work was supported by a JSPS Grant-in-Aid for JSPS Research Fellows 18J21936, the Takeda Science Foundation, a research award from the Japan Foundation for Aging and Health, NIG-JOINT [25A2019], a Grant-in-Aid for Scientific Research on Challenging Research (Exploratory) [JSPS KAKENHI Grant number 19K21593], a Grant-in-Aid for Scientific Research (B) [24K02860], a research grant from the National Institute of Aging/National Institutes of Health [RF1AG071557], and the TMU Strategic Research Fund.
