Central OC Times

Researchers led by the University of California, Irvine have discovered how the TREM2 R47H genetic mutation causes certain brain areas to develop abnormal protein clumps, known as beta-amyloid plaques, associated with late-onset Alzheimer’s disease. Utilizing single-cell Merfish spatial transcriptomics technology, the team profiled the effects of the mutation across multiple cortical and subcortical brain regions, providing unprecedented insights at the single-cell level.

The study, published online in the journal Molecular Psychiatry, compared brains of normal mice with those of special mouse models that undergo changes similar to humans with Alzheimer’s. Findings revealed that the TREM2 mutation led to different patterns of beta-amyloid plaque accumulation in various parts of the brain involved in higher-level functions such as memory, reasoning, and speech. It also affected certain cell types and their gene expression near these plaques.

“Alzheimer’s disease progresses differently in individuals with various genetic risk factors,” said principal investigator Xiangmin Xu, UC Irvine Chancellor’s Professor of anatomy and neurobiology and director of the campus’s Center for Neural Circuit Mapping. “By profiling known mutations, we can develop early, personalized treatments before cognitive decline begins.”

Team members analyzed 19 sections of mouse brains and more than 400,000 cells using Merfish technology to observe how they were affected by Alzheimer’s-related mutations. They examined gene expression patterns to understand regulation, cellular functions, and responses to stimuli. Their analysis showed that disparate mutations like TREM2 R47H cause changes in microglia and astrocyte cell reactions to inflammation and neuronal communication supporting brain health.

“Early intervention is key to preventing severe cognitive decline. This is the first study to look at the entire brain at such a detailed level,” Xu stated. “These insights can help develop targeted therapies that address these changes and lead to early intervention strategies that help prevent or slow down Alzheimer’s progression.”

The team was led by Kevin G. Johnston and associate researcher Zhiqun Tan from UC Irvine’s Department of Anatomy and Neurobiology. Other UC Irvine members included Kim Green; graduate student Kristine Minh Tran; Grant Macgregor; Zhaoxia Yu; Bereket Berackey; Eran A. Mukamel from UC San Diego; and Alon Gelber.

This work was supported by grants from the National Institutes of Health (R01 AG082127, U01 AG076791, R01 AG067153, U54 AG054349) and the National Institute on Deafness and Other Communication Disorders (T32 DC040775-14).

UC Irvine's Brilliant Future campaign aims to raise awareness and support for UC Irvine through engaging alumni and philanthropic investment. The School of Medicine plays a vital role in this campaign's success.

Founded in 1965, UC Irvine is ranked among the nation’s top 10 public universities by U.S. News & World Report. The campus has produced five Nobel laureates and contributes significantly to local and statewide economies.