Research from the Yale School of Medicine has uncovered a significant mechanism that may protect the brain from the damaging effects of Alzheimer’s disease. A study published in December 2023 in the journal JCI Insight identifies how the young brain utilizes a protein called Glyoxalase 1 (GLO1) to combat high levels of calcium that can be toxic to neurons.
The research team, led by Amy Arnsten, PhD, and Lauren Hachmann Sansing, MD, found that elevated levels of GLO1 in animal brains help mitigate the adverse effects of calcium dysregulation. While GLO1 acts as a protective agent against cellular toxins, the study revealed that its activity declines with age, potentially increasing the brain’s vulnerability to neurodegeneration.
Understanding Calcium Dysregulation
The study focuses on the role of calcium in the brain, particularly through a channel known as ryanodine receptor 2 (RyR2). This channel regulates calcium release from a cell’s smooth endoplasmic reticulum. According to Elizabeth Woo, an MD-PhD student and the study’s first author, “This channel is like a faucet that you can turn on and off.” When RyR2 becomes dysfunctional, it can lead to chronic calcium leakage, which has been linked to Alzheimer’s disease and even conditions like Long COVID.
In their research, the team utilized a genetically modified animal model where RyR2 was constantly activated, resulting in continuous calcium leakage. They observed elevated levels of GLO1 in both the prefrontal cortex and hippocampus—regions critical for cognition and memory. While GLO1 levels initially rose with age, they peaked at 12 months before declining in older animals.
The researchers tested memory in older animals using a T-shaped maze, finding that those without elevated GLO1 levels exhibited significantly impaired memory compared to their healthier counterparts. This supports the notion that calcium dysfunction is directly associated with cognitive decline.
Potential for Future Therapeutics
The findings from this study highlight GLO1’s role as a compensatory mechanism in the brain to counteract chronic calcium dysregulation. “Calcium is a very powerful mediator in the brain,” Woo explains. “GLO1 has detoxifying properties that can help the brain counter the changes in calcium over time.”
The implications of this research could be transformative. Understanding the protective measures that the brain has developed may lead to new therapeutic strategies aimed at preventing neurodegeneration before it takes hold. As Woo notes, “There’s a lot of important parallel research looking into how to treat Alzheimer’s disease once it’s developed. But as the upstream biology becomes clearer, we can also develop preventative therapeutics to target the disease before it becomes an issue.”
The collaborative effort between Arnsten’s and Sansing’s laboratories offers new insights into the biological processes preceding Alzheimer’s disease. As researchers continue to explore these pathways, the hope is to unlock potential treatments that could preserve cognitive function and enhance brain resilience as individuals age.
