by University of California, Irvine

MERFISH spatial transcriptomics enables spatial variation analysis of the transcriptome at the cell type level. A Dataset overview consisting of 15 samples, from WT, Trem2^R47H, 5xFAD and Trem2^R47H; 5xFAD mice. Cell counts in batch 1 are aggregated across two technical replicates, resulting in approximately double the cell counts of the other batches. B Integration of cell by gene matrix with RNA spatial location enables spatial analysis of transcriptomic variation on a regional and genotype basis. C 300 gene overlay on a single coronal section, at increasing resolutions. D UMAP displaying 37 annotated cell types after integration across all samples. E UMAP of cell genotypes. Note the distinct subpopulations specific to 5xFAD and Trem2^R47H; 5xFAD genotypes, particularly in microglia and astrocyte cell populations. F Hierarchical organization of cell clusters, combined with raw cell type proportions per genotype. Credit: Molecular Psychiatry (2024). DOI: 10.1038/s41380-024-02651-0

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, published in 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.

More information: Kevin G. Johnston et al, Single-cell spatial transcriptomics reveals distinct patterns of dysregulation in non-neuronal and neuronal cells induced by the Trem2R47H Alzheimer's risk gene mutation, Molecular Psychiatry (2024). DOI: 10.1038/s41380-024-02651-0

Journal information: Molecular Psychiatry 

Provided by University of California, Irvine