Cell type-specific changes identified by single-cell transcriptomics in Alzheimer’s disease

Abstract

The rapid advancement of single-cell transcriptomics in neurology has allowed for profiling of post-mortem human brain tissue across multiple diseases. Over the past 3 years, several studies have examined tissue from donors with and without diagnoses of Alzheimer’s disease, highlighting key changes in cell type composition and molecular signatures associated with pathology and, in some cases, cognitive decline. Although all of these studies have generated single-cell/nucleus RNA-seq or ATAC-seq data from the full array of major cell classes in the brain, they have each focused on changes in specific cell types. Here, we synthesize the main findings from these studies and contextualize them in the overall space of large-scale omics studies of Alzheimer’s disease. Finally, we touch upon new horizons in the field, in particular advancements in high-resolution spatial interrogation of tissue and multi-modal efforts—and how they are likely to further advance mechanistic and target-selection studies on Alzheimer’s disease.

Cellular dynamics across aged human brains uncover a multicellular cascade leading to Alzheimer’s disease

“…6). Previous snRNA-seq studies have associated cells and pathways to AD [4][5][6][7][8][9][10][11][12][13][14][15] , but were limited to a case-control study design and thus could neither infer cellular dynamics nor decouple AD and alternative aging. Because we use a sample of the older population and a prospective cohort study design, we leverage the full diversity of the older brain, allowing us to reconstitute the different trajectories of brain aging in a data-driven manner by applying BEYOND.…”

“…At the last stage of the AD cascade, we observed further increase in Mic.12 and Mic. 13 proportions, together with a coordinated increase of Ast.10 and Oli.13, with Ast.10 playing an important role mediating the effect of tau proteinopathy on the increased rate of cognitive decline. Both Ast.10 and Oli.13 express stress response genes, with Ast.10 mainly demonstrating response to oxidative stress while Oli.…”

“…Both Ast.10 and Oli.13 express stress response genes, with Ast.10 mainly demonstrating response to oxidative stress while Oli. 13 showing response to heat stress and unfolded protein. Cognitive decline appears to be directly affected by Ast.10 that is driven by both tau and Mic.13, suggesting that the proportion of this astrocyte subpopulation may be a point of convergence for different processes leading to cognitive dysfunction.…”

“…4h-j), matching the major classes expressing distinctive neuropeptides, such as somatostatin (SST, Inh.5-7), parvalbumin (PVALB, Inh. [13][14][15][16], vasoactive intestinal polypeptide (VIP, Inh.9-11) and KIT (Inh.2, Inh.4 and Inh.8).…”

“…However, bulk profiling of the brain parenchyma loses much of the information embedded in the intricate cellular architecture of the brain structures affected by AD. Single-cell and single-nucleus RNA-seq [4][5][6][7][8][9][10][11][12][13][14][15][16] have begun to offer a different perspective, underscoring the cellular perturbations that are part of the sequence of events leading to AD 17 . Currently, it appears that [4][5][6][7][8][9][10][11][12][13][14][15] : (1) changes in expression programs of multiple cell types, including glial, neuronal and vascular cells, are associated with AD, (2) within each cell type only specific subpopulations are likely to be actively involved in AD pathogenesis, and (3) AD-related expression programs changes are coordinated across multicellular communities of various cell subpopulations 4 .…”