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

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.

Bayesian estimation of cell type–specific gene expression with prior derived from single-cell data

“…5). These results paralleled results from unbiased snRNAseq data sets contrasting AD and control cell types, all of which revealed excitatory neurons as a rich source of DEGs (Mathys et al, 2019;Grubman et al, 2019;Lau et al, 2020). Furthermore, bMIND's CTS-DEGs showed significant overlap with a curated list of genes implicated in AD.…”

“…bMIND also identified notable enrichment of CTS-DEGs in astrocytes, highlighting gliogenesis, astrocyte differentiation/development, and glial cell proliferation. It did not, however, capture some important features of AD identified by snRNA-seq studies, including altered angiogenesis (Lau et al, 2020), age-differential microglial patterns of expression (Srinivasan et al, 2020), and role of oligodendrocytes in pathology (Mathys et al, 2019). With larger sample sizes and different brain regions sampled, we would expect that such features will emerge from future bMIND analyses of bulk gene expression.…”

Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment

“…We next evaluated the susceptibility of brain endothelial cells to SARS-CoV-2 infection and potential microvascular injury. For this, we analyzed the single-nuclei RNA-sequencing dataset from the prefrontal cortex region of 12 AD patients and 9 cognitively healthy controls [42] ( Fig. 4a ).…”

“…This single-nuclei RNA-sequencing dataset from the prefrontal cortex region of 12 AD patients and 9 normal controls [42] was used to test the susceptibility of brain endothelial cells to SARS-CoV-2 infection and damage. Six cell types were included: astrocytes, endothelial cells, excitatory neurons, inhibitory neurons, microglia, and oligodendrocytes.…”

Cholesterol, Atherosclerosis, and APOE in Vascular Contributions to Cognitive Impairment and Dementia (VCID): Potential Mechanisms and Therapy

“…Indeed, loss of BBB integrity and subsequent vasogenic edema are common consequences of acute ischemia (Yang et al, 2019 ). Moreover, chronic activation and retraction of pericytes and endothelial cells may perpetuate pre-existing neurodegeneration in humans (Lau et al, 2020 ; Montagne et al, 2020a ) and animal models (Bell et al, 2012 ). Various vascular risk factors are also associated with BBB damage (Cortes-Canteli and Iadecola, 2020 ).…”