Researchers have discovered that a single dose of a glycogen phosphorylase inhibitor can significantly improve spatial memory and affect brain metabolism in aged mice. This exciting finding suggests a potential new approach for addressing age-related cognitive decline. The study provides insights into the complex relationship between glycogen metabolism and neuroplasticity, offering hope for future therapies targeting brain aging.
Restoring Youthful Brain Function with a Single Dose
As we grow older, our cognitive abilities often decline. But what if a simple drug treatment could help reverse this process? That’s precisely what a team of researchers from Poland have discovered, using an unexpected target – the enzyme glycogen phosphorylase.
Glycogen phosphorylase is a key regulator of glycogen breakdown, the process that releases glucose from stored carbohydrates. The researchers found that inhibiting this enzyme with a compound called BAY U6751 had strikingly different effects on young versus aged mice.
In young mice, blocking glycogen phosphorylase actually impaired their spatial memory, as tested by the Novel Object Location (NOL) task. But in aged mice, the same single dose of the inhibitor significantly improved their performance on this hippocampus-dependent memory test.
The Metabolic Roots of Memory
To understand how this compound was able to rejuvenate the aged mouse brain, the researchers took a deep dive into the animals’ brain metabolism using nuclear magnetic resonance (NMR) spectroscopy. This powerful technique allowed them to identify and quantify a wide range of metabolites in different brain regions.
The data revealed that aging led to reductions in various metabolites involved in energy production, neurotransmitter signaling, and lipid metabolism within the hippocampus. Remarkably, the single dose of the glycogen phosphorylase inhibitor was able to reverse many of these age-related changes, restoring the levels of key molecules like alanine, phosphocreatine, GABA, and phosphoethanolamine.
A Balancing Act in the Aging Brain
The researchers propose that the inhibitor’s effects on spatial memory are linked to its ability to modulate the delicate balance of neurotransmitters and energy substrates in the hippocampus. In young animals, disrupting glycogen metabolism may tip this balance in an unfavorable way, impairing memory formation.
However, in aged mice, the metabolic landscape of the hippocampus has already shifted, with deficits in key signaling molecules and energy reserves. By restoring these parameters, the glycogen phosphorylase inhibitor appears to rejuvenate the aged brain, at least temporarily.
Implications for Combating Cognitive Decline
This study highlights the intricate relationship between neuroplasticity and cellular metabolism in the aging process. The findings suggest that targeting glycogen phosphorylase could be a promising avenue for developing therapies to combat age-related cognitive decline.
Moreover, the researchers’ use of unbiased metabolomic profiling provides a powerful tool for uncovering the complex metabolic shifts that occur in the aging brain. By gaining a deeper understanding of these processes, scientists may be able to identify additional targets and develop more effective interventions to support healthy brain aging.
Author credit: This article is based on research by Natalia Pudełko-Malik, Dominika Drulis-Fajdasz, Łukasz Pruss, Karolina Anna Mielko-Niziałek, Dariusz Rakus, Agnieszka Gizak, Piotr Młynarz.
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