Researchers at the University of California, Irvine have identified a new molecular interaction that changes current understanding of how brain inflammation develops in Alzheimer’s disease. The findings were published in the Proceedings of the National Academy of Sciences by a team led by assistant researcher Ruiming Zhao and Dr. Steve Goldstein, vice chancellor for health affairs at UC Irvine.
The study shows that amyloid precursor proteins (APP), which are known as the source of amyloid-beta peptides forming plaques in Alzheimer’s disease, form a complex with voltage-gated proton channels called Hv1 in human brain immune cells known as microglia. This discovery indicates that Hv1 receptor channels are structurally different than previously thought. When APP or its C99 transmembrane fragments bind to Hv1 channels, they increase proton currents and encourage microglia to release inflammatory mediators. Lowering APP expression reduces channel activity and the production of these inflammatory molecules.
The research also found that two mutations in APP associated with early-onset Alzheimer’s further raise channel activity, which may explain increased inflammation seen in those 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 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.”
Other contributors include Punyanuch Sophanpanichkul, Jean Paul Chadarevian, Yiwen Ding, Mathew Blurton-Jones, Hui Dai, Maha Nayak and Hayk Davtyan. The work involved collaboration between labs within UC Irvine’s Department of Neurobiology & Behavior, Institute for Memory Impairments and Neurological Disorders, and Sue & Bill Gross Stem Cell Research Center.
UC Irvine is recognized as one of the top 10 public universities nationally according to U.S. News & World Report and is a member of the Association of American Universities. The university employs more than 36,000 students across 224 degree programs and makes significant contributions to both local and state economies.
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