Wood, Jack;
Wong, Eugenia;
Joghee, Ridwaan;
Balbaa, Aya;
Vitanova, Karina S;
Vanshoiack, Alison;
Phelan, Stefan-Laural J;
... Edwards, Frances A; + view all
(2022)
Upregulation of Trem2 expression occurs exclusively on microglial contact with plaques.
BioRxiv: Cold Spring Harbor, NY, USA.
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Abstract
Using spatial cell-type-enriched transcriptomics, we compare plaque-induced gene (PIG) expression in microglia touching plaques, neighboring plaques, and far from plaques in 18-month-old APPNLF/NLF knock-in mice with and without the Alzheimer’s disease risk mutation Trem2R47H/R47H. We report that, in AppNLF/NLF mice, expression of 35/55 PIGs, is exclusively upregulated in microglia that are touching plaques. In 7 PIGs including Trem2 this upregulation is prevented by the Trem2R47H/R47H mutation. Unlike in young mice, knockin of the Trem2R47H/R47H mutation does not significantly decrease the Trem2 expression but decreases protein levels by 20% in the absence of plaques. On plaques, despite the mutation preventing increased gene expression, TREM2 protein levels increased by 1.6-fold (compared to 3-fold with Trem2WT/WT) and microglial density increased 20-fold compared to 30-fold. Hence microglia must touch plaques before Trem2 gene expression is increased but small changes in protein expression can increase microglia density without a change in gene expression.
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