Scientists at the University of California, Irvine, have uncovered a surprising new clue about how brain inflammation develops in Alzheimer’s disease.
Their discovery could change how researchers understand one of the key processes that damages the brain in this devastating condition.
In a new study published in the journal Proceedings of the National Academy of Sciences, researchers led by Dr. Steve Goldstein and assistant researcher Ruiming Zhao found that two very different kinds of proteins in the brain—amyloid precursor proteins and proton channels—work together in unexpected ways.
The partnership between these molecules appears to spark inflammation in brain immune cells, offering new insight into how Alzheimer’s disease progresses.
For decades, scientists have known that a protein called amyloid precursor protein, or APP, plays a major role in Alzheimer’s. APP breaks down into smaller fragments, including amyloid-beta peptides, which clump together to form sticky plaques in the brain.
These plaques are a hallmark of the disease and are linked to the death of brain cells and the loss of memory. But until now, researchers didn’t know that APP also connects directly with another key molecule inside the brain’s immune cells.
The UC Irvine team discovered that APP forms a physical and functional complex with voltage-gated proton channels known as Hv1. These channels help regulate electrical and chemical balance inside immune cells in the brain called microglia.
Microglia are the brain’s defense cells—they fight infection, clear debris, and respond to injury. But when they become overactive, they can also cause inflammation that harms brain tissue.
The researchers found that when APP or one of its fragments (known as C99) attaches to Hv1 channels, it changes how those channels work.
This connection increases the flow of protons through the channels, which in turn triggers the microglia to release inflammatory molecules. In other words, the interaction between APP and Hv1 may act like a molecular switch that turns up inflammation in the brain.
When the team used laboratory methods to reduce APP levels in human microglial cells, they saw the opposite effect—channel activity dropped, and the cells released far fewer inflammatory chemicals. This experiment showed that APP is not just a bystander in inflammation but an active player.
The researchers also studied APP mutations that are known to cause early-onset Alzheimer’s disease. They discovered that these mutations make the interaction with Hv1 channels even stronger, driving proton channel activity and inflammation to higher levels than normal.
This may help explain why patients with inherited forms of Alzheimer’s experience faster and more severe brain damage.
Dr. Goldstein, the study’s senior author and vice chancellor for health affairs at UC Irvine, said the finding came as a complete surprise. “Hv1 has long been known to control inflammation in immune cells, but to discover that APP—a protein at the center of Alzheimer’s—directly modifies its behavior was unexpected,” he said.
“This finding starts to explain why these channels behave differently in different tissues, and that’s key to figuring out how to target them safely in future treatments.”
This new understanding of how APP influences inflammation could open the door to more precise therapies. Many past Alzheimer’s treatments have focused on reducing amyloid plaques, but those efforts have had limited success.
By targeting the inflammatory process at its source—in this case, the APP-Hv1 interaction—scientists may find new ways to slow or prevent brain damage before it becomes irreversible.
The research was carried out by a team from UC Irvine’s Biodesign Center for Biomaterials Innovation and Translation, the Department of Neurobiology & Behavior, the Institute for Memory Impairments and Neurological Disorders, and the Sue & Bill Gross Stem Cell Research Center.
The collaboration included scientists Punyanuch Sophanpanichkul, Jean Paul Chadarevian, Yiwen Ding, Mathew Blurton-Jones, Hui Dai, Maha Nayak, and Hayk Davtyan.
In summary, this discovery shines new light on how inflammation takes root in the Alzheimer’s brain.
By revealing that amyloid precursor proteins directly influence proton channels in immune cells, the study helps connect two previously separate pieces of the Alzheimer’s puzzle—and may bring us a step closer to effective new treatments.
If you care about Alzheimer’s, please read studies about Vitamin D deficiency linked to Alzheimer’s, vascular dementia, and Oral cannabis extract may help reduce Alzheimer’s symptoms.
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