Remarkable new findings about the sugar stores in neurons have unlocked an entire new method of treating Alzheimer’s disease and other cognitive decline, and it goes a long way to explaining why there’s a growing body of evidence linking GLP-1 weight loss drugs to protection from dementia.
Scientists at the Buck Institute for Research on Aging made this discovery when investigating the often overlooked glycogen stores in our neurons, which has largely been viewed as a redundant aspect of our biology until now. The researchers found that the metabolism of this sugar – a stored form of glucose – appears to protect the brain from toxic tau build-up and cognitive decline.
“This new study challenges that view, and it does so with striking implications,” said Pankaj Kapahi, a professor and senior scientist on the study. “Stored glycogen doesn’t just sit there in the brain; it is involved in pathology.”
If you didn’t know you had a stash of sugar in your neurons, it won’t be a surprise; glycogen is otherwise stored in muscles and the liver, where we better understand its function. This is partly because the brain’s stores are very small, so they didn’t seem to have much of a role at all. However, on closer inspection, the researchers saw just how important they might be to brain health.
The team first made these findings in fruit flies, but the discovery also translated to human cells that modeled tau build-up. When tau – one of the main culprits in the progression of Alzheimer’s disease – amasses, the neurons get stuck with extra sugar that can’t be broken down by normal metabolic processes. The “clumps” spoken about in Alzheimer’s diagnoses seem to bind to glycogen, which impedes the sugar from being used. So it builds up, along with more tau proteins.
When the glycogen can’t be broken down, then neurons are blocked from managing oxidative stress – another bad sign when it comes to neurodegeneration. However, boosting a particular enzyme, glycogen phosphorylase (GlyP), can get the ball rolling and clear out that excess sugar, in turn stopping tau from clinging to it.
“By increasing GlyP activity, the brain cells could better detoxify harmful reactive oxygen species, thereby reducing damage and even extending the lifespan of tauopathy model flies,” said study lead Sudipta Bar.
But in addition to these novel findings, the team also noted how GlyP levels are boosted naturally by fasting behaviors. And the same boost could be triggered by GLP-1 RA weight-loss and diabetes drugs.
“This work could explain why GLP-1 drugs, now widely used for weight loss, show promise against dementia, potentially by mimicking dietary restriction,” said Kapahi.
This mechanism is made more efficient by higher levels of GlyP, which the researchers were able to demonstrate in human neurons sourced from frontotemporal dementia (FTD) patients, and shows that this treatment could benefit those with neurodegenerative conditions by kickstarting the cleaning process that had otherwise come to a halt.
Overall, this study furthers our understanding of glycogen stores and how healthy neurons can quickly degenerate if the conditions for impeding metabolism are present. And that relieving symptoms of dementia or even preventing its onset could be achieved with current obesity medicines.
“By discovering how neurons manage sugar, we may have unearthed a novel therapeutic strategy: one that targets the cell’s inner chemistry to fight age-related decline,” said Kapahi. “As we continue to age as a society, findings like these offer hope that better understanding – and perhaps rebalancing – our brain’s hidden sugar code could unlock powerful tools for combating dementia.”
The study was published in the journal Nature Metabolism.
Source: Buck Institute for Research on Aging via EurekAlert!
