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Genetic Mutation

UC Irvine-led team reveals how TREM2 genetic mutation affects late-onset Alzheimer’s

First-of-their-kind insights into brain effects could yield new targets for early intervention

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, called beta-amyloid plaques, associated with late-onset Alzheimer’s disease. Leveraging single-cell Merfish spatial transcriptomics technology, the team was able to profile the effects of the mutation across multiple cortical and subcortical brain regions, offering first-of-their-kind insights at the single-cell level.

The study, recently published online in the journal Molecular Psychiatry, compared the brains of normal mice and special mouse models that undergo changes like those in humans with Alzheimer’s.

Findings revealed that the TREM2 mutation led to divergent 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 the 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 a special technique called Merfish to see how they were affected by the Alzheimer’s-related mutations. They were able to examine the expression patterns of genes, providing insight into how they are regulated, contribute to cellular functions and respond to stimuli. Their analysis showed that disparate mutations, like TREM2 R47H, cause changes in the ways microglia and astrocyte cells react to inflammation, as well as how neurons communicate and support 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, enabling us to gain a deeper understanding of how the TREM2 R47H mutation impacts gene expression in specific cell types,” Xu said. “These insights can help develop targeted therapies that address these changes and can lead to early intervention strategies that help prevent or slow down the progression of Alzheimer’s disease.”

The team was led by Kevin G. Johnston, until recently a postdoctoral scholar, and associate researcher Zhiqun Tan from UC Irvine’s Department of Anatomy and Neurobiology. Other UC Irvine members included Kim Green, professor and vice chair, and graduate student Kristine Minh Tran from the Department of Neurobiology and Behavior; Grant Macgregor, professor of developmental and cell biology; Zhaoxia Yu, professor of statistics; and Bereket Berackey, biomedical engineering graduate student researcher. Eran A. Mukamel, associate professor of cognitive science, and Alon Gelber, M.D.-Ph.D. candidate, from UC San Diego also participated.

This work was supported by the National Institutes of Health under grants R01 AG082127, U01 AG076791, R01 AG067153, U54 AG054349 and RF 1 AG065675; and the National Institute on Deafness and Other Communication Disorders under grant T32 DC040775-14.

UC Irvine’s Brilliant Future campaign: Publicly launched on Oct. 4, 2019, the Brilliant Future campaign aims to raise awareness and support for UC Irvine. By engaging 75,000 alumni and garnering $2 billion in philanthropic investment, UC Irvine seeks to reach new heights of excellence in student success, health and wellness, research and more. The School of Medicine plays a vital role in the success of the campaign. Learn more by visiting https://brilliantfuture.uci.edu/uci-school-of-medicine.

About the University of California, Irvine: Founded in 1965, UC Irvine is a member of the prestigious Association of American Universities and is ranked among the nation’s top 10 public universities by U.S. News & World Report. The campus has produced five Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UC Irvine has more than 36,000 students and offers 224 degree programs. It’s located in one of the world’s safest and most economically vibrant communities and is Orange County’s second-largest employer, contributing $7 billion annually to the local economy and $8 billion statewide. For more on UC Irvine, visit www.uci.edu.

Media access: Radio programs/stations may, for a fee, use an on-campus studio with a Comrex IP audio codec to interview UC Irvine faculty and experts, subject to availability and university approval. For more UC Irvine news, visit news.uci.edu. Additional resources for journalists may be found at https://news.uci.edu/media-resources.

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