A single cell brain atlas in human Alzheimer’s disease

Abstract

26Alzheimer's disease (AD) is a heterogeneous disease that is largely dependent on the complex 27 cellular microenvironment in the brain. This complexity impedes our understanding of how 28 individual cell types contribute to disease progression and outcome. To characterize the 29 molecular and functional cell diversity in the human AD brain we utilized single nuclei RNA-30 seq in AD and control patient brains in order to map the landscape of cellular heterogeneity in 31 AD. We detail gene expression changes at the level of cells and cell subclusters, highlighting 32 specific cellular contributions to global gene expression patterns between control and 33 Alzheimer's patient brains. We observed distinct cellular regulation of APOE which was 34 repressed in oligodendrocyte progenitor cells (OPCs) and astrocyte AD subclusters, and highly 35 enriched in a microglial AD subcluster. In addition, oligodendrocyte and microglia AD 36 subclusters show discordant expression of APOE. Integration of transcription factor regulatory 37 modules with downstream GWAS gene targets revealed subcluster-specific control of AD cell 38 fate transitions. For example, this analysis uncovered that astrocyte diversity in AD was under 39 the control of transcription factor EB (TFEB), a master regulator of lysosomal function and 40 which initiated a regulatory cascade containing multiple AD GWAS genes. These results 41 establish functional links between specific cellular sub-populations in AD, and provide new 42 insights into the coordinated control of AD GWAS genes and their cell-type specific 43 contribution to disease susceptibility. Finally, we created an interactive reference web resource 44 which will facilitate brain and AD researchers to explore the molecular architecture of subtype 45 and AD-specific cell identity, molecular and functional diversity at the single cell level. 46Highlights 47 • We generated the first human single cell transcriptome in AD patient brains 48 • Our study unveiled 9 clusters of cell-type specific and common gene expression 49 patterns between control and AD brains, including clusters of genes that present 50 properties of different cell types (i.e. astrocytes and oligodendrocytes) 51 • Our analyses also uncovered functionally specialized sub-cellular clusters: 5 52 microglial clusters, 8 astrocyte clusters, 6 neuronal clusters, 6 oligodendrocyte 53 clusters, 4 OPC and 2 endothelial clusters, each enriched for specific ontological 54 gene categories 55 • Our analyses found manifold AD GWAS genes specifically associated with one 56 cell-type, and sets of AD GWAS genes co-ordinately and differentially regulated 57 between different brain cell-types in AD sub-cellular clusters 58 • We mapped the regulatory landscape driving transcriptional changes in AD brain, 59 and identified transcription factor networks which we predict to control cell fate 60 transitions between control and AD sub-cellular clusters 61 • Finally, we provide an interactive web-resource that allows the user to further 62 visua...

Zonation-dependent single-endothelial cell transcriptomic changes in the aged brain

“…We also noted upregulation of Dlc1 in aged capEC ( Fig. 3), which has also been identified as an upregulated gene in human AD patient brain ECs 56 . Our data thus support that AD has a unique vascular ageing component, especially in the capillary endothelium, among other neurodegenerative diseases.…”

An Integrative Network-based Analysis Reveals Gene Networks, Biological Mechanisms, and Novel Drug Targets in Alzheimer’s Disease

“…Genetic signals for AD are enriched in microglial cells [32], which themselves only account for around 3% of the total brain cell population. Therefore, RNA sequencing of individualised cells (known as single cell RNA sequencing) may partition genetic signals to causal cell types and improve power to identify functional genes and mechanisms underlying AD and, in turn, improve the accuracy of drug positioning [6].…”

“…Gene expression is an intermediate molecular phenotype that is directly modified by DNA sequence variation (expression quantitative trait loci; eQTLs), epigenetic marks such as DNA methylation, and the environment, as well as the expression of other genes [4]. Gene expression analyses of post-mortem brain tissue have identified distinct cell types and biological pathways underlying AD pathogenesis [5,6].…”

Differential transcript usage unravels gene expression alterations in Alzheimer’s disease human brains

“…Recent work has begun to address this important gap in the study of AD pathology using bulk brain tissue RNA sequencing (RNAseq) (T. Raj et al, 2018) or single-cells RNA sequencing (scRNAseq) (Grubman et al, 2019;Mathys et al, 2019). However, these studies have focused on samples obtained from different brain regions, namely the dorsolateral prefrontal (Mathys et al, 2019;T.…”

“…However, these studies have focused on samples obtained from different brain regions, namely the dorsolateral prefrontal (Mathys et al, 2019;T. Raj et al, 2018) and entorhinal cortices (Grubman et al, 2019), which could lead to important discrepancies in the results. Indeed, the AD pathology shows a progressive impact on different brain regions, characterized at early stages by the presence of TAU protein inclusions in the locus coeruleus, the transentorhinal and entorhinal regions (stages I and II).…”