Exploring the feasibility of using mice as a substitute model for investigating microglia in aging and Alzheimer's disease though single cell analysis.

Abstract

To guide animal experiments, we investigated the similarities and differences between humans and mice in aging and Alzheimer's disease (AD) at the single-nucleus RNA sequencing (snRNA-seq) or single-cell RNA sequencing (scRNA-seq) level. Microglia cells were extracted from dataset GSE198323 of human post-mortem hippocampus. The distributions and proportions of microglia subpopulation cell numbers related to AD or age were compared. This comparison was done between GSE198323 for humans and GSE127892 for mice, respectively. The Seurat R package and harmony R package were used for data analysis and batch effect correction. Differentially expressed genes (DEGs) were identified by FindMarkers function with MAST test. Comparative analyses were conducted on shared genes in DEGs associated with age and AD. The analyses were done between human and mouse using various bioinformatics techniques. The analysis of genes in DEGs related to age was conducted. Similarly, the analysis of genes in DEGs related to AD was performed. Cross-species analyses were conducted using orthologous genes. Comparative analyses of pseudotime between humans and mice were performed using Monocle2. (1) Similarities: The proportion of microglial subpopulation Cell_APOE/Apoe shows consistent trends, whether in AD or normal control (NC) groups in both humans and mice. The proportion of Cell_CX3CR1/Cx3cr1, representing homeostatic microglia, remains stable with age in NC groups across species. Tuberculosis and Fc gamma R-mediated phagocytosis pathways are shared in microglia responses to age and AD across species, respectively. (2) Differences: IL1RAPL1 and SPP1 as marker genes are more identifiable in human microglia compared to their mouse counterparts. Most genes of DEGs associated with age or AD exhibit different trends between humans and mice. Pseudotime analyses demonstrate varying cell density trends in microglial subpopulations, depending on age or AD across species. Mouse Apoe and Cell_Apoe maybe serve as proxies for studying human AD, while Cx3cr1 and Cell_Cx3cr1 are suitable for human aging studies. However, AD mouse models (App_NL_G_F) have limitations in studying human genes like IL1RAPL1 and SPP1 related to AD. Thus, mouse models cannot fully replace human samples for AD and aging research.