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Single-cell spatial transcriptomics of an inducible destabilized-domain Cre mouse line to target disease associated microglia

Henningfield, Caden1; Kwang, Nellie1; Green, Kim1

Published Oct 28, 2025 on Dryad. https://doi.org/10.5061/dryad.15dv41p9d

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Abstract

This dataset contains the results from a single-cell spatial transcriptomics experiment performed using Bruker Nanostring CosMx technology on 10µm thick fresh-frozen coronal brain sections from the following groups: 5xFAD hemizygous, Cst7 DD-Cre, Ai14tdTomato double heterozygous (AD, n = 3), and Cst7 DD-Cre/Ai14tdTomato double heterozygous (WT, n = 1) mice treated with TMP, and Cst7 DD-Cre/Ai14tdTomato double heterozygous mice treated with cuprizone (CPZ) and TMP (CPZ, n = 2). The dataset is provided as an .RDS file, which includes raw and corrected counts, along with comprehensive metadata. Metadata includes experimental group, sample ID, cell type annotations, and X-Y coordinates of each cell.

The function of microglia during progression of Alzheimer's disease (AD) can be investigated using mouse models that enable genetic manipulation of microglial subpopulations in a temporal manner. We developed mouse lines that express either Cre recombinase (Cre) for constitutive targeting, or destabilized-domain Cre recombinase (DD-Cre) for inducible targeting from the Cst7 locus (Cst7 DD-Cre) to specifically manipulate disease associated microglia (DAM) and crossed with Ai14 tdTomato cre-reporter line mice. Cst7Cre was found to target all brain resident myeloid cells, due to transient developmental expression of Cst7, but no expression was found in the inducible Cst7 DD-Cre mice. Further crossing of this line with 5xFAD mice combined with dietary administration of trimethoprim to induce DD-Cre activity produces long-term labeling in DAM without evidence of leakiness, with tdTomato-expression restricted to cells surrounding plaques. Using this model, we found that DAMs are a subset of plaque-associated microglia (PAMs) and their transition to DAM increases with age and disease stage. Spatial transcriptomic analysis revealed that tdTomato+ cells show higher expression of disease and inflammatory genes compared to other microglial populations, including non-labeled PAMs. These models allow either complete cre-loxP targeting of all brain myeloid cells (Cst7Cre), or inducible targeting of DAMs, without leakiness (Cst7 DD-Cre).