A single-cell atlas of entorhinal cortex from individuals with Alzheimer's disease reveals cell-type-specific gene expression regulation.
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
Author Information
- Alexandra Grubman: Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia. ORCID
- Gabriel Chew: Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School, Singapore, Singapore.
- John F Ouyang: Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School, Singapore, Singapore. ORCID
- Guizhi Sun: Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.
- Xin Yi Choo: Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia. ORCID
- Catriona McLean: Victorian Brain Bank, Florey Institute of Neurosciences, Parkville, Victoria, Australia. ORCID
- Rebecca K Simmons: ARC Center of Excellence in Plant Energy Biology, The University of Western Australia, Perth, Western Australia, Australia.
- Sam Buckberry: ARC Center of Excellence in Plant Energy Biology, The University of Western Australia, Perth, Western Australia, Australia.
- Dulce B Vargas-Landin: ARC Center of Excellence in Plant Energy Biology, The University of Western Australia, Perth, Western Australia, Australia. ORCID
- Daniel Poppe: ARC Center of Excellence in Plant Energy Biology, The University of Western Australia, Perth, Western Australia, Australia.
- Jahnvi Pflueger: ARC Center of Excellence in Plant Energy Biology, The University of Western Australia, Perth, Western Australia, Australia.
- Ryan Lister: ARC Center of Excellence in Plant Energy Biology, The University of Western Australia, Perth, Western Australia, Australia. ORCID
- Owen J L Rackham: Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School, Singapore, Singapore. owen.rackham@duke-nus.edu.sg. ORCID
- Enrico Petretto: Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Medical School, Singapore, Singapore. enrico.petretto@duke-nus.edu.sg. ORCID
- Jose M Polo: Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia. jose.polo@monash.edu. ORCID
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.
Alzheimer Disease
Apolipoproteins E
Astrocytes
Atlases as Topic
Case-Control Studies
Down-Regulation
Entorhinal Cortex
Female
Gene Expression Regulation
Genetic Predisposition to Disease
Humans
Male
Microglia
Oligodendrocyte Precursor Cells
Sequence Analysis, RNA
Up-Regulation
