Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 41; pp. 25800 - 25809
• Main Authors: Lau, Shun-Fat, Cao, Han, Fu, Amy K. Y., Ip, Nancy Y.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 13.10.2020
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Angiogenesis; Antigen presentation; Antigens; Astrocytes; Biological activity; Biological Sciences; Brain; Cell Nucleus - genetics; Dementia disorders; Endothelial cells; Endothelial Cells - cytology; Endothelial Cells - metabolism; Female; Gene expression; Gene Expression Profiling; Growth factors; Heterogeneity; Histocompatibility antigen HLA; Humans; Immune response; Immune system; Male; Myelination; Neurodegenerative diseases; Neuroglia - cytology; Neuroglia - metabolism; Neuronal-glial interactions; Neuroprotection; Nuclei (cytology); Oligodendrocytes; Pathogenesis; Prefrontal Cortex - cytology; Prefrontal Cortex - metabolism; Single-Cell Analysis; Transcriptome; myelination; neurodegenerative diseases; synaptic signaling; synapse; angiogenesis
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2008762117

Alzheimer’s disease (AD) is the most common form of dementia but has no effective treatment. A comprehensive investigation of cell type-specific responses and cellular heterogeneity in AD is required to provide precise molecular and cellular targets for therapeutic development. Accordingly, we perform single-nucleus transcriptome analysis of 169,496 nuclei from the prefrontal cortical samples of AD patients and normal control (NC) subjects. Differential analysis shows that the cell type-specific transcriptomic changes in AD are associated with the disruption of biological processes including angiogenesis, immune activation, synaptic signaling, and myelination. Subcluster analysis reveals that compared to NC brains, AD brains contain fewer neuroprotective astrocytes and oligodendrocytes. Importantly, our findings show that a subpopulation of angiogenic endothelial cells is induced in the brain in patients with AD. These angiogenic endothelial cells exhibit increased expression of angiogenic growth factors and their receptors (i.e., EGFL7, FLT1, and VWF) and antigen-presentation machinery (i.e., B2M and HLA-E). This suggests that these endothelial cells contribute to angiogenesis and immune response in AD pathogenesis. Thus, our comprehensive molecular profiling of brain samples from patients with AD reveals previously unknown molecular changes as well as cellular targets that potentially underlie the functional dysregulation of endothelial cells, astrocytes, and oligodendrocytes in AD, providing important insights for therapeutic development.