Spatiotemporal transcriptomic characterization of an amyloid mouse model of Alzheimer’s disease

Background Transcriptomic studies of Alzheimer's disease (AD) have identified both tissue‐level and cell‐type specific gene expression changes. However, with both "bulk"‐tissue and single‐cell approaches, we lose pertinent spatial information, such as cell‐to‐cell proximity or proximity to pathological features. Recently several techniques have emerged, aiming to profile gene expression while preserving the spatial architecture, and we have leveraged one of these techniques—spatial transcriptomics—to interrogate AD gene expression changes in the 5XFAD, an amyloid mouse model, in a spatial and temporal manner. Methods We generated spatial transcriptomic (10x Genomics Visium) data from 5XFAD and wildtype mice at the ages of 4, 6, 8, and 12 months (n = 80 total samples, sex‐balanced). Prior to generating libraries, we stained our tissue sections with Amylo‐glo and the conformation‐specific antibody OC to analyze gene expression changes in spatial relativity to amyloid pathology. Results We profiled 18,000‐20,000 total genes per sample with 1,800‐2,700 genes per spatial spot and identified brain region‐specific transcriptionally distinct clusters. We also examined the spatial distribution of AD risk genes, identified by GWAS, throughout the disease progression. Further, we identified gene expression changes spatially related to amyloid pathology localization. Conclusions We have characterized the 5XFAD transcriptome, identifying spatiotemporal AD gene expression changes and providing further insight into the role of amyloid pathology in the modulation of gene expression in AD.