HMN 2025: How the brain protects itself from Alzheimer’s disease

High levels of calcium are toxic to cells and contribute to loss of neurons in Alzheimer’s disease. A new study published in JCI Insight identifies a mechanism through which the young brain protects itself against high calcium levels, and it could help scientists learn how to protect the brain from this devastating neurodegenerative condition.

Glyoxalase 1 (GLO1) is a protein that plays an essential role in getting rid of toxic byproducts in cells. In the study, Yale School of Medicine (YSM) researchers discovered elevated GLO1 levels in the brains of animals with excessive levels of cellular calcium, finding that the brain increased GLO1 expression as a protective mechanism to mitigate the effects of the calcium dysregulation.

However, with advancing age, GLO1 activity declined, the researchers found, which may make the brain less resilient to neurodegeneration. The study could inform the development of therapeutics that target GLO1 and prevent neurodegeneration.

“We discovered how the brain itself deals with calcium leak and uses a resilience factor that erodes with age,” says Amy Arnsten, Ph.D., Albert E. Kent Professor of Neuroscience and the study’s co-principal investigator. “If we could keep this mechanism going, we’d be protecting the brain in a way that the brain itself has devised.”

The study was a collaboration between Arnsten’s laboratory and the laboratory of Lauren Hachmann Sansing, MD, professor of neurology at YSM.

How calcium dysregulation impacts the brain

Arnsten’s laboratory focuses on calcium dysregulation at a channel known as ryanodine receptor 2 (RyR2), which releases calcium from storage within a cell’s smooth endoplasmic reticulum. “This channel is like a faucet that you can turn on and off,” says Elizabeth Woo, an MD-Ph.D. student at YSM and the study’s first author. “It can cause calcium to come out into the neuron, which has many downstream effects.”

Previous research has shown that RyR2 can become altered with age so that the faucet is constantly “on,” and that these changes are associated with Alzheimer’s disease and even Long COVID. In their new study, the researchers explored how the brain responds to this unregulated influx of calcium.

The team used an animal model in which RyR2 was genetically altered to always be “on,” causing chronic calcium leakage in the brain. They observed elevated GLO1 expression and activity in both the prefrontal cortex and hippocampus, two regions that are important for cognition and memory. GLO1 expression initially increased with age, peaking at 12 months in mice, but then declined in older animals.

Then, the researchers introduced the older animals to a T-shaped maze designed to test their memory. They found that those with genetically modified RyR2 receptors who no longer had elevated GLO1 had worse memory compared to their healthy counterparts.

The findings confirmed that calcium dysfunction is associated with worsened cognition.

The study points to GLO1 expression as a potential mechanism in the brain to compensate for chronic calcium dysregulation. “Calcium is a very powerful mediator in the brain,” says Woo. “GLO1 has detoxifying properties that can help the brain counter the changes in calcium over time.”

The researchers are hopeful that uncovering the processes preceding Alzheimer’s disease could one day lead to new therapies.

“There’s a lot of important parallel research looking into how to treat Alzheimer’s disease once it’s developed,” Woo says. “But as the upstream biology becomes clearer, we can also develop preventative therapeutics to target the disease before it becomes an issue.”

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