Impact of non-neuronal cells in Alzheimer's disease from a single-nucleus profiling perspective

Abstract

The role of non-neuronal cells has been relatively overlooked in Alzheimer's disease (AD) neuropathogenesis compared to neuronal cells since the first characterization of the disease. Genome wide-association studies (GWAS) performed in the last few decades have greatly contributed to highlighting the critical impact of non-neuronal cells in AD by uncovering major genetic risk factors that are found largely in these cell types. The recent development of single cell or single nucleus technologies has revolutionized the way we interrogate the transcriptomic and epigenetic profiles of neurons, microglia, astrocytes, oligodendrocytes, pericytes, and endothelial cells simultaneously in the same sample and in an individual manner. Here, we review the latest advances in single-cell/nucleus RNA sequencing and Assay for Transposase-Accessible Chromatin (ATAC) sequencing to more accurately understand the function of non-neuronal cells in AD. We conclude by giving an overview of what still needs to be achieved to better appreciate the interconnected roles of each cell type in the context of AD.

Keywords: Alzheimer’s disease; astrocytes; endothelial cells; microglia; neurons; oligodendrocytes; pericytes; single-nucleus RNA-seq.

FIGURE 1

Schematic summary of microglial states in AD patients and mouse models. Genes upregulated (green) and downregulated (red) in snRNA-seq and snATAC-seq studies when comparing AD patients or 5xFAD mice with their respective controls. IRF8, interferon regulatory factor 8; SORL1, sortilin related receptor 1; A2M, alpha-2 macroglobulin; CHI3L1, chitinase 3 like 1; CD68, CD74, CD83, and CD86, cluster of differentiation 68, 74, 83 and 86; CX3CR1, C-X3-C motif chemokine receptor 1; P2RY12, purinergic receptor P2Y12; LPAR6, lysophosphatidic acid receptor 6; GPR183, G protein-coupled receptor 183; SPP1, secreted phosphoprotein 1; AXL, AXL receptor tyrosine kinase; CSF1, colony stimulating factor 1; CLEC7A, C-type lectin domain containing 7A; CST7, Cystatin F; GPNMB, glycoprotein nmb; IGF1, insulin like growth factor 1; ITGAX, integrin subunit alpha X; TYROBP, transmembrane immune signaling adaptor TYROBP; C3, complement C3; LPL, Lipoprotein lipase; TMEM119, transmembrane protein 119.

FIGURE 2

Schematic overview of astrocyte states influenced by microglia activation state in AD patients and mouse models. Genes upregulated (green) and downregulated (red) in snRNA-seq and snATAC-seq studies when comparing AD patients or 5xFAD mice with their respective controls. STAT2, signal transducer and activator of transcription 2; NF-κB, nuclear factor kappa B subunit 1; BIN1, bridging integrator 1; GFAP, glial fibrillary acidic protein; SYTL4, synaptotagmin like 4; SLC1A2, solute carrier family 1 member 2; PLXNB1, plexin B1; PLEKHA5, pleckstrin homology domain containing A5; VCAN, versican; ADAMTSL3, ADAMTS like 3; PLCE1, phospholipase C epsilon 1; NCAN, neurocan; COL5A3, collagen Type V alpha 3 chain; C4B, complement C4B; ApoE, apolipoprotein E; GRIA2, glutamate ionotropic receptor AMPA type subunit 2; GRM3, glutamate metabotropic receptor 3; KCNIP4, potassium voltage-gated channel interacting protein 4; LRRC7, leucine rich repeat containing 7; SMURF2, SMAD specific E3 ubiquitin protein ligase 2; FABP5, fatty acid binding protein 5; HILPDA, hypoxia inducible lipid droplet associated; SOD2, superoxide dismutase 2; VIM, vimentin; SERPINA3, serpin family A member 3.

FIGURE 3

Schematic summary of oligodendrocyte states in AD patients and mouse models, which lead to degeneration of myelin. Genes upregulated (green) and downregulated (red) in snRNA-seq and snATAC-seq studies when comparing AD patients or 5xFAD mice with their respective controls. NRF1, Nuclear respiratory factor 1; LINGO1, leucine rich repeat and Ig domain-containing 1; PLP1, proteolipid protein 1; OLIG1, oligodendrocyte transcription factor 1; MBP, myelin basic protein; SREBF1, sterol regulatory element binding transcription factor 1; SYT1, synaptotagmin-1; NRGN, neurogranin; SNAP25, synaptosome associated protein 25; KCNH8, potassium voltage-gated channel subfamily H member 8; B2M, beta-2 microglobulin; H2-D1, histocompatibility 2, D region locus 1; SERPINA3N, Serine (or cysteine) peptidase inhibitor, clade A, member 3N; OXTi, oxytocini; ITGAX, integrin alpha X; CST7, cystatin F; CCL6, chemokine (C-C motif) ligand 6.

FIGURE 4

Schematic overview of the blood-brain-barrier cells (endothelial cells, pericytes and astrocytes) in AD patients and mouse models. Genes upregulated (green) and downregulated (red) in snRNA-seq and snATAC-seq studies when comparing AD patients or 5xFAD mice with their respective controls. EGFL7, EGF like domain multiple 7; FLT1, Fms related receptor tyrosine kinase 1; VWF, von willebrand factor; MHC-I, major histocompatibility complex I; HLA-E, major histocompatibility complex, class I, E; B2M, beta-2-microglobulin; CLDN5, claudin 5; SLC2A1, solute carrier family 2 member 1; NFAT, nuclear factor of activated T-cells.