A single-cell atlas of entorhinal cortex from individuals with Alzheimer’s disease reveals cell-type-specific gene expression regulation

Grubman, Alexandra; Chew, Gabriel; Ouyang, John F.; Sun, Guizhi; Choo, Xin Yi; McLean, Catriona; Simmons, Rebecca K.; Buckberry, Sam; Vargas-Landin, Dulce B; Poppe, Daniel; Pflueger, Jahnvi; Lister, Ryan; Rackham, Owen J. L.; Petretto, Enrico; Polo, José M.

doi:10.1038/s41593-019-0539-4

Cited by 632 publications

(803 citation statements)

References 67 publications

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“…Our analysis yielded 24,735 brain nuclei profiles and provide a resource to better understand the complex cellular interactions and gene expression profiles that may contribute to the pathogenesis of CTE. Similar to previous reports using snRNA-seq in other neurological diseases, including Alzheimer's disease (AD), multiple sclerosis (MS), autism spectrum disorder (ASD), and epilepsy (Mathys et al 2019;Grubman et al 2019;Jäkel et al 2019;Schirmer et al 2019;Velmeshev et al 2019), our findings indicate changes in cell types, subpopulations, and gene expression in CTE. Our findings are the first report of molecular and cellular changes at single nucleus resolution in CTE.…”

Section: Introductionsupporting

confidence: 90%

“…High-throughput single cell resolution genomics is an ideal tool for assessing the complexity of human brain diseases (Mathys et al 2019;Jäkel et al 2019;Velmeshev et al 2019;Grubman et al 2019;Nagy et al 2020). To better understand the pathobiology of white matter alterations in CTE, we performed a single nucleus RNA-seq (Habib et al 2017) (snRNAseq) analysis of dorsolateral frontal white matter in subjects with neuropathologically confirmed CTE and compared the results to age-matched controls.…”

Section: Introductionmentioning

confidence: 99%

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Altered oligodendroglia and astroglia in chronic traumatic encephalopathy

Chancellor

Duke-Cohan

et al. 2020

Preprint

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Chronic traumatic encephalopathy (CTE) is a progressive tauopathy found in contact sport athletes, military veterans, and others exposed to repetitive head injury (McKee et al. 2009(McKee et al. , 2013(McKee et al. , 2016Omalu et al. 2005Omalu et al. , 2006Martland 1928;Critchley 1949). White matter atrophy and axonal loss have been reported in CTE but have not been characterized on a molecular or cellular level (McKee et al. 2013;Holleran et al. 2017;Hsu et al. 2018). Here, we report 24,735 single nucleus RNA-seq profiles from dorsolateral frontal white matter cell nuclei from eight individuals with neuropathologically confirmed CTE and eight age-and sex-matched controls. We identified eighteen transcriptionally distinct nuclei clusters, as well as cell-type-specific differences between conditions. The findings support a global loss of oligodendrocytes (OLs) in CTE, alterations in OL subpopulations, and suggest pathological iron accumulation in OL subpopulations. Total astrocyte number was not different between CTE and controls but showed upregulation of transcripts associated with neuroinflammation. These findings provide novel insight into the molecular and cellular underpinnings of white matter atrophy in CTE, which may lead to an improved understanding of the disease pathogenesis.

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Section: Introductionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Altered oligodendroglia and astroglia in chronic traumatic encephalopathy

Chancellor

Duke-Cohan

et al. 2020

Preprint

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“…It is also important to note that both sequencing studies previously mentioned utilized different mouse lines to identify OPCs than the PDGFRα-Cre ER ; R26-EYFP used in this study, which may have also contributed to the difference between our dataset and the previous observations of a homogenous population of OPCs. Excitingly, recent sequencing data from human Alzheimer's disease patients and healthy controls demonstrated that healthy controls have three subpopulations of OPCs, and that one of these populations expressed high levels of Clusterin, one of the genes we identified as significantly upregulated in OPC1 59 . Additionally, single-cell sequencing data from human patients at fetal, adolescent, and adult timepoints reveal multiple transcriptionally distinct populations of oligo-lineage cells that largely clustered based on the age of the patient 60 .…”

Section: Discussionmentioning

confidence: 89%

“…While we describe the transcriptional profile of OPCs during homeostasis, it is important to note that understanding the role of OPCs in the healthy brain will provide a necessary foundation for examining any protective or detrimental novel functions in desease pathology. Previous work has demonstrated that OPCs exhibit significant transcriptional heterogeneity and disease-associated signatures in models of multiple sclerosis and cerebral ischemia, and showed significant transcriptional changes in human Alzheimer's disease patients 18,59,76 .…”

Section: Discussionmentioning

confidence: 99%

Oligomeric amyloid beta prevents myelination in a clusterin-dependent manner

Beiter

Fernández-Castañeda

Rivet-Noor

et al. 2020

Preprint

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Oligodendrocyte progenitor cells (OPCs) are a mitotically active population of glia that comprise approximately 5% of the adult brain. OPCs maintain their proliferative capacity and ability to differentiate in oligodendrocytes throughout adulthood, but relatively few mature oligodendrocytes are produced following developmental myelination. Recent work has begun to demonstrate that OPCs likely perform multiple functions in both homeostasis and disease, and can significantly impact behavioral phenotypes such as food intake and depressive symptoms. However, the exact mechanisms through which OPCs might influence brain function remains unclear. In this work, we demonstrate that OPCs are transcriptionally diverse and separate into three distinct populations in the homeostatic brain. These three groups show distinct transcriptional signatures and enrichment of biological processes unique to individual OPC populations. We have validated these OPC populations using multiple methods, including multiplex RNA in situ hybridization and RNA flow cytometry. This study provides an important resource that profiles the transcriptome of adult OPCs and will provide a significant foundation for further investigation into novel OPC functions.

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“…In single-cell studies, pathway activation analysis has become a powerful approach for extracting biologically relevant signatures to uncover the potential mechanisms of cell heterogeneity and dysfunction in human diseases (8,9). For example, the pathway signatures exhibit the significant activation difference in breast cancer (10) and Alzheimer's disease cells (11) using gene set enrichment analysis. However, there is a lack of online web server for the comprehensive analysis and visualization of single-cell transcriptome data based on prior biological pathway knowledge.…”

Section: Introductionmentioning

confidence: 99%

scTPA: A web tool for single-cell transcriptome analysis of pathway activation signatures

Zhang

et al. 2020

Preprint

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The most fundamental challenge in current single-cell RNA-seq data analysis is functional interpretation and annotation of cell clusters. The biological pathways in distinct cell types have different activation patterns, which facilitates understanding cell functions in single-cell transcriptomics. However, no effective web tool has been implemented for single-cell transcriptomic data analysis based on prior biological pathway knowledge. Here, we introduce scTPA (http://sctpa.bio-data.cn/sctpa), which is a web-based platform providing pathway-based analysis of single-cell RNA-seq data in human and mouse. scTPA incorporates four widely-used gene set enrichment methods to estimate the pathway activation scores of single cells based on a collection of available biological pathways with different functional and taxonomic classifications. The clustering analysis and cell-type-specific activation pathway identification were provided for the functional interpretation of cell types from pathway-oriented perspective. An intuitive interface allows users to conveniently visualize and download single-cell pathway signatures. Together, scTPA is a comprehensive tool to identify pathway activation signatures for dissecting single cell heterogeneity.

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A single-cell atlas of entorhinal cortex from individuals with Alzheimer’s disease reveals cell-type-specific gene expression regulation

Cited by 632 publications

References 67 publications

Altered oligodendroglia and astroglia in chronic traumatic encephalopathy

Altered oligodendroglia and astroglia in chronic traumatic encephalopathy

Oligomeric amyloid beta prevents myelination in a clusterin-dependent manner

scTPA: A web tool for single-cell transcriptome analysis of pathway activation signatures

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