A Single-cell Atlas of Entorhinal Cortex from Individuals with Alzheimer's Disease Reveals Cell-type-specific Gene Expression Regulation

Overview

Journal Nat Neurosci

Date 2019 Nov 27

PMID 31768052

Citations 443

Authors

Alexandra Grubman

Gabriel Chew

John F Ouyang

Guizhi Sun

Xin Yi Choo

Catriona McLean

Rebecca K Simmons

Sam Buckberry

Dulce B Vargas-Landin

Daniel Poppe

Jahnvi Pflueger

Ryan Lister

Owen J L Rackham

Enrico Petretto

Jose M Polo

Affiliations

Soon will be listed here.

Abstract

There is currently little information available about how individual cell types contribute to Alzheimer's disease. Here we applied single-nucleus RNA sequencing to entorhinal cortex samples from control and Alzheimer's disease brains (n = 6 per group), yielding a total of 13,214 high-quality nuclei. We detail cell-type-specific gene expression patterns, unveiling how transcriptional changes in specific cell subpopulations are associated with Alzheimer's disease. We report that the Alzheimer's disease risk gene APOE is specifically repressed in Alzheimer's disease oligodendrocyte progenitor cells and astrocyte subpopulations and upregulated in an Alzheimer's disease-specific microglial subopulation. Integrating transcription factor regulatory modules with Alzheimer's disease risk loci revealed drivers of cell-type-specific state transitions towards Alzheimer's disease. For example, transcription factor EB, a master regulator of lysosomal function, regulates multiple disease genes in a specific Alzheimer's disease astrocyte subpopulation. These results provide insights into the coordinated control of Alzheimer's disease risk genes and their cell-type-specific contribution to disease susceptibility. These results are available at http://adsn.ddnetbio.com.

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