TREM2遺伝子変異が遅発性アルツハイマー病にどのように影響するかを解明(UC Irvine-led team reveals how TREM2 genetic mutation affects late-onset Alzheimer’s)

204-08-06 カリフォルニア大学校アーバイン校(UCI)

<関連情報>

• https://news.uci.edu/2024/08/06/uc-irvine-led-team-reveals-how-trem2-genetic-mutation-affects-late-onset-alzheimers/
• https://www.nature.com/articles/s41380-024-02651-0

単一細胞空間トランスクリプトミクスにより、Trem2R47Hアルツハイマー病リスク遺伝子変異によって誘導される非神経細胞および神経細胞における調節異常の異なるパターンが明らかになる Single-cell spatial transcriptomics reveals distinct patterns of dysregulation in non-neuronal and neuronal cells induced by the Trem2R47H Alzheimer’s risk gene mutation

Kevin G. Johnston,Bereket T. Berackey,Kristine M. Tran,Alon Gelber,Zhaoxia Yu,Grant R. MacGregor,Eran A. Mukamel,Zhiqun Tan,Kim N. Green & Xiangmin Xu
Molecular Psychiatry  Published:05 August 2024
DOI:https://doi.org/10.1038/s41380-024-02651-0

Abstract

The R47H missense mutation of the TREM2 gene is a known risk factor for development of Alzheimer’s Disease. In this study, we analyze the impact of the Trem2^R47H mutation on specific cell types in multiple cortical and subcortical brain regions in the context of wild-type and 5xFAD mouse background. We profile 19 mouse brain sections consisting of wild-type, Trem2^R47H, 5xFAD and Trem2^R47H; 5xFAD genotypes using MERFISH spatial transcriptomics, a technique that enables subcellular profiling of spatial gene expression. Spatial transcriptomics and neuropathology data are analyzed using our custom pipeline to identify plaque and Trem2^R47H-induced transcriptomic dysregulation. We initially analyze cell type-specific transcriptomic alterations induced by plaque proximity. Next, we analyze spatial distributions of disease associated microglia and astrocytes, and how they vary between 5xFAD and Trem2^R47H; 5xFAD mouse models. Finally, we analyze the impact of the Trem2^R47H mutation on neuronal transcriptomes. The Trem2^R47H mutation induces consistent upregulation of Bdnf and Ntrk2 across many cortical excitatory neuron types, independent of amyloid pathology. Spatial investigation of genotype enriched subclusters identified spatially localized neuronal subpopulations reduced in 5xFAD and Trem2^R47H; 5xFAD mice. Overall, our MERFISH spatial transcriptomics analysis identifies glial and neuronal transcriptomic alterations induced independently by 5xFAD and Trem2^R47H mutations, impacting inflammatory responses in microglia and astrocytes, and activity and BDNF signaling in neurons.