Upregulation of Trem2 expression occurs exclusively on microglial contact with plaques

Wood, J.; Wong, E.; Joghee, R.; Balbaa, A.; Vitanova, K. S.; Vanshoiack, A.; Phelan, S.-L. J.; Launchbury, F.; Desai, S.; Tripathi, T.; Hanrieder, J.; Cummings, D. M.; Hardy, J.; Edwards, F. A.

doi:10.1101/2022.01.26.477873

bioRxiv · 10.1101/2022.01.26.477873

Upregulation of Trem2 expression occurs exclusively on microglial contact with plaques

Wood, J.·Wong, E.·Joghee, R.·Balbaa, A.·Vitanova, K. S.·Vanshoiack, A.·Phelan, S.-L. J.·Launchbury, F.·Desai, S.·Tripathi, T.·Hanrieder, J.·Cummings, D. M.·Hardy, J.·Edwards, F. A.

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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 Alzheimers 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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Wood, J., Wong, E., Joghee, R., Balbaa, A., Vitanova, K. S., Vanshoiack, A., Phelan, S.-L. J., Launchbury, F., Desai, S., Tripathi, T., Hanrieder, J., Cummings, D. M., Hardy, J., Edwards, F. A.. 2022-01-28. Upregulation of Trem2 expression occurs exclusively on microglial contact with plaques. https://doi.org/10.1101/2022.01.26.477873

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