Revealing cell vulnerability in Alzheimer's disease by single-cell transcriptomics

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder that by affecting specific brain cell types and regions cause severe pathological and functional changes in memory neural circuits. A comprehensive knowledge of the pathogenic mechanisms underlying AD requires a deeper understanding of the cell-specific pathological responses through integrative molecular analyses. Recent application of high-throughput single-cell transcriptomics to postmortem tissue has proved powerful to unravel cell susceptibility and biological networks responding to amyloid and tau pathologies. Here, we review single-cell transcriptomic studies successfully applied to decipher cell-specific gene expression programs and pathways in the brain of AD patients. Transcriptional information reveals both specific and common gene signatures affecting the major cerebral cell types, including astrocytes, endothelial cells, microglia, neurons, and oligodendrocytes. Cell type-specific transcriptomes associated with AD pathology and clinical symptoms are related to common biological networks affecting, among others pathways, synaptic function, inflammation, proteostasis, cell death, oxidative stress, and myelination. The general picture that emerges from systems-level single-cell transcriptomics is a spatiotemporal pattern of cell diversity and biological pathways, and novel cell subpopulations affected in AD brain. We argue that broader implementation of cell transcriptomics in larger AD human cohorts using standardized protocols is fundamental for reliable assessment of temporal and regional cell-type gene profiling. The possibility of applying this methodology for personalized medicine in clinics is still challenging but opens new roads for future diagnosis and treatment in dementia.