Format

Send to

Choose Destination
Nature. 2019 Jun;570(7761):332-337. doi: 10.1038/s41586-019-1195-2. Epub 2019 May 1.

Single-cell transcriptomic analysis of Alzheimer's disease.

Author information

1
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
2
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA.
3
MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA, USA.
4
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
5
Department of Neurology, Harvard Medical School, Boston, MA, USA.
6
Evergrande Center for Immunologic Diseases, Harvard Medical School, Boston, MA, USA.
7
Third Rock Ventures, Boston, MA, USA.
8
Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
9
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
10
MIT Computer Science and Artificial Intelligence Laboratory, Cambridge, MA, USA. manoli@mit.edu.
11
Broad Institute of MIT and Harvard, Cambridge, MA, USA. manoli@mit.edu.
12
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA. lhtsai@mit.edu.
13
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA. lhtsai@mit.edu.
14
Broad Institute of MIT and Harvard, Cambridge, MA, USA. lhtsai@mit.edu.

Abstract

Alzheimer's disease is a pervasive neurodegenerative disorder, the molecular complexity of which remains poorly understood. Here, we analysed 80,660 single-nucleus transcriptomes from the prefrontal cortex of 48 individuals with varying degrees of Alzheimer's disease pathology. Across six major brain cell types, we identified transcriptionally distinct subpopulations, including those associated with pathology and characterized by regulators of myelination, inflammation, and neuron survival. The strongest disease-associated changes appeared early in pathological progression and were highly cell-type specific, whereas genes upregulated at late stages were common across cell types and primarily involved in the global stress response. Notably, we found that female cells were overrepresented in disease-associated subpopulations, and that transcriptional responses were substantially different between sexes in several cell types, including oligodendrocytes. Overall, myelination-related processes were recurrently perturbed in multiple cell types, suggesting that myelination has a key role in Alzheimer's disease pathophysiology. Our single-cell transcriptomic resource provides a blueprint for interrogating the molecular and cellular basis of Alzheimer's disease.

PMID:
31042697
DOI:
10.1038/s41586-019-1195-2

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center