Neuropathological lesions in the brains of individuals affected with neurodegenerative disorders are hypothesized to trigger molecular and cellular processes that disturb the homeostasis of local microenvironments. Here, we applied the 10x Genomics Visium Spatial Proteogenomics (Visium-SPG) platform, which couples spatial gene expression with immunofluorescence (IF) protein co-detection, to evaluate its ability to quantify changes in spatial gene expression with respect to amyloid-beta (Aβ) and hyperphosphorylated tau (pTau) pathology in post-mortem human brain tissue from individuals with Alzheimer's disease (AD). We identified transcriptomic signatures associated with proximity to Aβ in the human inferior temporal cortex during late-stage AD, which we further investigated at cellular resolution with combined IF and single-molecule fluorescent in situ hybridization (smFISH). The study provides a data analysis workflow for Visium-SPG, and the data represent a proof-of-principle for the power of multi-omic profiling in identifying changes in molecular dynamics that are spatially associated with pathology in the human brain. We provide the scientific community with web-based, interactive resources to access the datasets of the spatially resolved AD-related transcriptomes.
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