Spatial and single-nucleus transcriptomic analysis of genetic and sporadic forms of Alzheimer’s Disease

Abstract

The pathogenesis of Alzheimer's disease (AD) depends on environmental and heritable factors, with remarkable differences evident between individuals at the molecular level. Here we present a transcriptomic survey of AD using spatial transcrip- tomics (ST) and single-nucleus RNA-seq in cortical samples from early-stage AD, late-stage AD, and AD in Down Syndrome (AD in DS) donors. Studying AD in DS provides an opportunity to enhance our understanding of the AD transcriptome, potentially bridging the gap between genetic mouse models and sporadic AD. Our analysis revealed spatial and cell-type specific changes in disease, with broad similarities in these changes between sAD and AD in DS. We performed additional ST experiments in a disease time-course of 5xFAD and wild-type mice to facilitate cross-species comparisons. Finally, amyloid plaque and fibril imaging in the same tissue samples used for ST enabled us to directly link changes in gene expression with accumulation and spread of pathology.

Single-nucleus and spatial transcriptomic profiling of human temporal cortex and white matter reveals novel associations with AD pathology

“…We integrated our dataset from TC region (GM and WM) to other published studies from different brain regions that include entorhinal cortex 10,11 (Leng et al 8 , Grubman et al 9 ), prefrontal cortex 12,13,5 (Cain et al 12 , Zhou et al 13 , Mathys et al 5 ), superior frontal gyrus 10 (Leng et al 10 ) and deep white matter from prefrontal cortex 12 (Cain et al 12 ). The matrix of filtered UMI counts (>500) for each study was converted to a single cell experiment (SCE) object using the function read10xCounts from SingleCellExperiment 45 package on R (version 4.0.1) platform.…”

“…Although the complex pathophysiology of AD remains poorly understood, recent transcriptomic and epigenomic analyses have revealed that post-mortem human AD brain tissue exhibits downregulation of genes associated with neuronal function 4,5 and upregulation of the genes involved in the innate immune response 6,7 . However, not many studies have looked systematically at the spatial distribution of gene expression and its relationship to neuropathology 8 . Thus, our overall understanding of cell type heterogeneity and compositional changes during pathological accumulation is still under-explored, hindering our ability to understand the biological processes underlying AD 9 .…”

Gene networks and systems biology in Alzheimer's disease: Insights from multi‐omics approaches

“…(2021), Miyoshi et al. (2023), and Seattle Alzheimer's Disease Brain Cell Atlas (SEA‐AD), 23 , 42 , 55 , 56 , 57 , 58 totaling 349 samples, 1.3 million cells, and 25k genes after the initial QC process (Figure 1B ). While analysis approaches are continually evolving, we have adopted the following workflow for single cell/nucleus RNA‐seq studies, inspired by the guidelines by Luecken et al.…”

“…For demonstrating the pipeline, we have merged snRNA-seq data from the following publications in the field of AD and dementia asso- Alzheimer's Disease Brain Cell Atlas (SEA-AD), 23,42,[55][56][57][58] totaling 349 samples, 1.3 million cells, and 25k genes after the initial QC process (Figure 1B). While analysis approaches are continually evolving, we have adopted the following workflow for single cell/nucleus RNA-seq F I G U R E 1 Schematic workflow of single-cell/nucleus data acquisition and analysis.…”

Down Syndrome Biobank Consortium: A perspective

“…DS is both a neurodevelopmental and neurodegenerative disorder and and artificial intelligence with machine learning, will allow unique indepth analysis of these valuable brain tissues as reported by members of the DSBC (e.g., 55 ).…”