Researchers at Yale School of Medicine have made significant strides in understanding how the brain protects itself against the damaging effects of high calcium levels, a key factor in the progression of Alzheimer’s disease. A recent study published in JCI Insight identifies a crucial protein, Glyoxalase 1 (GLO1), which appears to enhance the brain’s resilience against calcium dysregulation. This discovery may pave the way for new therapeutic approaches to combat neurodegenerative conditions.
The study highlights that elevated calcium levels are toxic to neurons and contribute to their loss in Alzheimer’s disease. Researchers found that animals with excessive cellular calcium exhibited increased levels of GLO1, indicating the brain’s attempt to counteract the harmful effects of calcium overload. However, as age progresses, the activity of GLO1 declines, potentially diminishing the brain’s ability to resist neurodegeneration.
Amy Arnsten, PhD, Albert E. Kent Professor of Neuroscience and co-principal investigator of the study, emphasized the significance of their findings. “We discovered how the brain itself deals with calcium leak and uses a resilience factor that erodes with age,” Arnsten stated. The collaborative research effort included Lauren Hachmann Sansing, MD, a professor of neurology at Yale, underscoring the study’s comprehensive approach.
Understanding Calcium Dysregulation in the Brain
Calcium dysregulation is a critical area of focus in Arnsten’s laboratory, particularly concerning the ryanodine receptor 2 (RyR2). This channel, which releases calcium from the smooth endoplasmic reticulum within cells, can become dysfunctional with age. “This channel is like a faucet that you can turn on and off,” explained Elizabeth Woo, an MD-PhD student at Yale and the study’s first author. “It can cause calcium to come out into the neuron, which has many downstream effects.”
Previous research has indicated that age-related alterations to RyR2 can lead to chronic calcium leakage, a condition associated with both Alzheimer’s disease and Long COVID. This study aimed to investigate the brain’s response to this unregulated calcium influx. Researchers utilized an animal model in which RyR2 was genetically modified to remain permanently “on,” resulting in persistent calcium leakage.
They observed that GLO1 expression and activity increased in critical brain areas, including the prefrontal cortex and hippocampus—regions vital for cognition and memory. GLO1 levels peaked at 12 months of age in mice but subsequently declined in older specimens. This decline correlated with cognitive impairment, as demonstrated in memory tests using a T-shaped maze.
The results reaffirm the link between calcium dysfunction and cognitive decline. “Calcium is a very powerful mediator in the brain,” Woo noted, highlighting GLO1’s detoxifying properties that help mitigate adverse calcium effects over time.
Potential for Preventative Therapeutics
The implications of this research extend beyond immediate treatment options for Alzheimer’s disease. The findings suggest a potential mechanism for compensating chronic calcium dysregulation, presenting an opportunity for developing preventative therapies. “There’s a lot of important parallel research looking into how to treat Alzheimer’s disease once it’s developed,” Woo remarked. “But as the upstream biology becomes clearer, we can also develop preventative therapeutics to target the disease before it becomes an issue.”
As the scientific community continues to unravel the complexities of Alzheimer’s disease, this study highlights the importance of understanding the brain’s inherent protective mechanisms. By targeting proteins like GLO1, researchers hope to create innovative strategies that could enhance brain resilience, offering a proactive approach to tackling neurodegeneration.
The study was shared by Isabella Backman, a senior science writer and editor at Yale School of Medicine, emphasizing the institution’s commitment to advancing knowledge in neuroscience and its potential applications for human health.
