Abstract
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.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia but has no effective treatment
The results indicated that there is a loss of neuroprotective glial cells in AD, which may contribute to impaired neurotransmitter recycling in astrocytes, demyelination in oligodendrocytes, and perturbed synaptic pruning in microglia
Our results reveal that the cell type-specific transcriptomic changes in AD are associated with four molecular pathways: angiogenesis in endothelial cells, immune response in endothelial cells and microglia, myelination in oligodendrocytes, and synaptic signaling in astrocytes and neurons (Fig. 2E)
Summary
Alzheimer’s disease (AD) is the most common form of dementia but has no effective treatment. 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. Recent studies utilized single-nucleus transcriptome analysis to investigate the transcriptomic changes in AD brains [12,13,14] and have revealed molecular alterations at the single-cell level using readily available frozen brain tissues Such studies identified the dysregulated pathways in the most predominant neural cell types, such as neurons and oligodendrocytes, in AD. In order to comprehensively investigate the dysregulated molecular pathways in different cell types in AD and determine the cellular targets that contribute to the observed changes, we performed single-nucleus transcriptome analysis of the AD brain by profiling 169,496 nuclei from AD patients and healthy normal control (NC) subjects.
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