Researchers led by UC Irvine have made a significant discovery in understanding the TREM2 R47H genetic mutation’s effect on Alzheimer’s disease, which could pave the way for groundbreaking early interventions and therapies.
In a pioneering study that could reshape the future of Alzheimer’s treatment, a research team led by the University of California, Irvine has unveiled how the TREM2 R47H genetic mutation drives the development of beta-amyloid plaques, crucial in the progression of late-onset Alzheimer’s disease. Utilizing advanced single-cell Merfish spatial transcriptomics technology, this investigation provides unprecedented insights into the mutation’s effects at the cellular level.
Published in the journal Molecular Psychiatry, the study offers a detailed comparison between normal mice and genetically altered mouse models mirroring human Alzheimer’s conditions. The discovery highlighted how the TREM2 mutation disrupted beta-amyloid plaque accumulation patterns in various brain regions responsible for memory, reasoning and speech. It further showed distinct impacts on cell types and their gene expressions in the vicinity of these plaques.
“Alzheimer’s disease progresses differently in individuals with various genetic risk factors,” Xiangmin Xu, a professor of anatomy and neurobiology at UC Irvine and the study’s principal investigator, said in a news release. “By profiling known mutations, we can develop early, personalized treatments before cognitive decline begins.”
The team meticulously analyzed 19 sections of mouse brains and over 400,000 cells using the Merfish technique. This cutting-edge analysis allowed them to observe gene expression patterns and their regulation, significantly advancing the understanding of cellular functions and reactions to stimuli in Alzheimer’s disease. The TREM2 R47H mutation, in particular, led to changes in how microglia and astrocyte cells responded to inflammation and how neurons communicated, revealing critical pathways involved in disease progression.
“Early intervention is key to preventing severe cognitive decline,” Xu added. “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. 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 research was spearheaded by postdoctoral scholar Kevin G. Johnston and associate researcher Zhiqun Tan from UC Irvine’s Department of Anatomy and Neurobiology. Contributing members included experts from UC Irvine’s Department of Neurobiology and Behavior, Department of Developmental and Cell Biology and Department of Statistics, along with collaborators from UC San Diego.
The study’s implications are profound, offering a new avenue for therapeutic strategies. By identifying the specific genetic and cellular changes caused by the TREM2 mutation, the research paves the way for personalized medicine approaches that could significantly improve outcomes for Alzheimer’s patients. The work, funded by various National Institutes of Health grants, represents a beacon of hope in the battle against this devastating disease.