Study uncovers how TREM2 R47H mutation affects Alzheimer’s plaques

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

The study, recently published online in the journal Molecular psychiatrycompared the brains of normal mice with special mouse models that undergo changes like those in people with Alzheimer’s disease.

Findings showed that the TREM2 mutation led to divergent patterns of beta-amyloid plaque accumulation in different 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 different genetic risk factors. By profiling known mutations, we can develop early, personalized treatments before cognitive decline begins.”

Xiangmin Xu, principal investigator, UC Irvine Chancellor’s Professor of Anatomy and Neurobiology and director of the campus’s Center for Neural Circuit Mapping

Team members analyzed 19 mouse brain sections and more than 400,000 cells using a special technique called Merfish to see how they were affected by the Alzheimer’s disease-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 found that disparate mutations, such as TREM2 R47H, cause changes in the way microglia and astrocyte cells respond to inflammation, as well as in the way neurons communicate and support brain health.

“Early intervention is key to preventing severe cognitive decline. This is the first study to look at the whole brain at such a detailed level, allowing us to gain a deeper understanding of how the TREM2 R47H mutation affects gene expression in specific cell types.” said Xu. “These insights could help develop targeted therapies that address these changes and lead to early intervention strategies that help prevent or slow the progression of Alzheimer’s disease.”

The team was led by Kevin G. Johnston, until recently a postdoctoral researcher, and Associate Professor Zhiqun Tan of 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 of the Department of Neurobiology and Behavior; Grant Macgregor, professor of developmental and cell biology; Zhaoxia Yu, professor of statistics; and Bereket Berackey, graduate student researcher in biomedical engineering. Eran A. Mukamel, associate professor of cognitive sciences, and Alon Gelber, MD-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.