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Significance Alzheimer’s disease (AD) has complex pathological mechanisms. Our limited understanding of the molecular and cellular changes in AD hindered the identification of therapeutic targets. In this study, we profiled 169,496 nuclei from the prefrontal cortical samples of AD patients and healthy controls by single-nucleus RNA sequencing. 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. Moreover, the analysis revealed a role of antigen presentation by angiogenic endothelial cells in AD. Together, our findings offer important insights into the therapeutic potential of targeting glial- and endothelial-specific pathways to restore brain homeostasis in AD.
Lau et al. (Mon,) studied this question.