Irvine, Calif., Oct. 23, 2025 — In a groundbreaking study that could reshape the scientific understanding of Alzheimer’s disease, researchers at the University of California, Irvine, have discovered a novel molecular interaction that contributes to brain inflammation associated with the condition. The findings, published today in the Proceedings of the National Academy of Sciences, highlight a previously unknown partnership between amyloid precursor proteins and voltage-gated proton channels in brain immune cells.
The research, led by assistant researcher Ruiming Zhao and Dr. Steve Goldstein, vice chancellor for health affairs at UC Irvine, reveals that amyloid precursor proteins, typically known for their role in forming amyloid-beta plaques, also form a complex with Hv1 receptor channels in microglia. This discovery not only changes the understanding of Hv1 channel composition but also their functional properties within the brain, impacting neuroinflammation and neurodegeneration in Alzheimer’s patients.
The Molecular Discovery
This new insight into the molecular dynamics of Alzheimer’s disease was supported by the National Institutes of Health and the Cure Alzheimer’s Fund. The study demonstrates that when amyloid precursor proteins or their C99 fragments bind to Hv1 channels, they enhance proton currents and promote the release of inflammatory mediators from microglia derived from human induced pluripotent stem cells. Conversely, reducing amyloid precursor protein expression significantly decreases channel activity and inflammatory molecule production.
Notably, the research team identified that two mutations in amyloid precursor proteins, associated with early-onset Alzheimer’s, further amplify channel activity, potentially explaining the increased inflammation observed in these patients.
“Hv1 has long been known to control inflammation in immune cells, but to discover that APP – a protein at the center of Alzheimer’s pathology – directly modifies its behavior was completely unexpected,” said Dr. Goldstein, senior author of the study. “This finding is exciting because it starts to explain why Hv1 channels operate differently in different tissues in health, information we need to target them effectively to treat disease.”
Implications for Alzheimer’s Research
The implications of this discovery are profound, offering a new avenue for understanding and potentially treating Alzheimer’s disease. By elucidating the role of Hv1 channels in neuroinflammation, this research could pave the way for targeted therapies that modulate these channels to mitigate inflammation and slow disease progression.
The study was a collaborative effort involving the Zhao-Goldstein laboratory, Blurton-Jones’ lab in UC Irvine’s Department of Neurobiology & Behavior, the Institute for Memory Impairments and Neurological Disorders, and the Sue & Bill Gross Stem Cell Research Center. The authors include Punyanuch Sophanpanichkul, Jean Paul Chadarevian, Yiwen Ding, Mathew Blurton-Jones, Hui Dai, Maha Nayak, and Hayk Davtyan.
About UC Irvine
Founded in 1965, the University of California, Irvine is a member of the prestigious Association of American Universities and consistently ranks among the nation’s top public universities. Known for its academic excellence and innovative research, UC Irvine has produced five Nobel laureates and offers 224 degree programs to its over 36,000 students. Located in one of the world’s safest and most economically vibrant communities, UC Irvine is Orange County’s second-largest employer, contributing significantly to the local and state economy.
For more information about UC Irvine and its research initiatives, visit www.uci.edu. Journalists can access additional resources at news.uci.edu/media-resources.
