Journal
NATURE NEUROSCIENCE
Volume 22, Issue 12, Pages 2087-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41593-019-0539-4
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Funding
- Florey Institute of Neuroscience and Mental Health
- Alfred
- Victorian Institute of Forensic Medicine
- Parkinson's Victoria
- MND Victoria
- State Government of Victoria
- Australian Government
- Dementia Australia Research Foundation Grant
- Monash Network of Excellence grant
- Yulgilbar Foundation grant
- National Health and Medical Research Council (NHMRC)
- Australian Research Council (ARC) Dementia Research Development Fellowship [GNT1097461, GNT1111206]
- Sylvia-Charles Viertel Fellowship
- Singapore National Research Foundation Competitive Research Programme [NRF-CRP20-2017-0002]
- Sylvia and Charles Viertel Senior Medical Research Fellowship
- Howard Hughes Medical Institute International Research Scholarship
- MRC [MC_U120097112] Funding Source: UKRI
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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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