Table 1 Summary of recent studies on AD utilizing single-cell RNA sequencing
From: The interaction between ageing and Alzheimer's disease: insights from the hallmarks of ageing
Study and year | Platform | Region | Data accessibility | Main findings |
|---|---|---|---|---|
Keren-Shaul et al. 2017 [264] | Illumina NextSeq 500 sequencer | Whole brains of 5xFAD mice and C57/BL6 mice | GEO: GSE98969 (single-cell RNA-seq) and GEO: GSE98970 (iChIP) | A novel microglial type associated with neurodegenerative diseases was described. The markers, spatial localisation and pathways associated with this cell type were identified |
Mathys et al. 2017 [265] | Illumina HiSeq 2000 platform | Hippocampus of AD mice and control mice | GEO: GSE103334 | Two molecularly distinct phenotypes of reactive microglia were identified, characterized by modules of co-regulated type I and type II interferon response genes, respectively. The study also identified heterogeneity in microglial responses to neurodegeneration, disease stage-specific microglial states, cell reprogramming trajectory of microglial response to neurodegeneration and the underlying transcriptional pathways |
Mathys et al. 2019 [259] | 10× Genomics platform | Prefrontal cortex of patients with AD and healthy individuals | https://www.radc.rush.edu/docs/omics.htm (snRNA-seq PFC) | The study identified different transcriptomic subsets, including those associated with pathology, characterised by regulators of myelination, inflammation and neuronal survival. The strongest disease-related changes occur early in the progression of AD and are highly cell type-specific, whereas in the later stages of AD, different cell types show similar upregulation of genes, mainly those involved in stress responses |
Cosacak et al. 2019 [266] | 10× Genomics platform | Zebrafish brain | GEO: GSE118577 | The study provided extensive data on the molecular basis of NSC plasticity in the brains of adult zebrafish models of AD |
Gate et al. 2020 [260] | Illumina HiSeq 4000 platform | Peripheral blood mononuclear cells of 97 healthy individuals, 31 patients with MCI, 28 patients with AD and 8 patients with PD | GEO: GSE134578 | The immune-related features of AD included an increase in the number of CD8+ T effector memory CD45RA+ (TEMRA) cells, and the proportion of CD8+ TEMRA cells was negatively associated with cognitive function. In addition, single-cell RNA sequencing showed that T cell receptor signalling was enhanced in these cells. The findings revealed adaptive immune responses in the blood and cerebrospinal fluid of patients with AD and provided evidence that cloned, antigen-experienced T cells patrol the intracranial space of the brain affected by age-related neurodegenerative diseases |
Zhong et al. 2020 [267] | Illumina Hiseq-PE150 platform | Hippocampus of APP23 mice | GEO: GSE141044 | Comparative transcription analysis revealed various changes in different subtypes of hippocampal neurons in APP23 mice compared with control mice, and validated transcriptional changes in these neurons during disease progression |
Xu et al. 2020 [268] | Illumina NovaSeq 6000 platform | Peripheral blood mononuclear cells of amyloid-positive AD patients and amyloid-negative healthy individuals | GEO: GSE181279 | Five immune cell subsets were revealed: CD4+ T cells, CD8+ T cells, B cells, natural killer cells and mononuclear macrophages. The characteristic changes in the proportions of these cell subsets and their gene expression patterns in AD were revealed. Protein–protein interaction network and pathway enrichment analyses revealed 31 cell type-specific key genes, including abundant human leukocyte antigen genes and multiple immune-related pathways. The study also revealed high-frequency amplification clones of T and B cells and decreased T cell diversity in AD. As clonal amplification suggests the activation of adaptive immune responses to specific antigens, the finding suggests that peripheral adaptive immune responses, especially those mediated by T cells, may play a role in the pathogenesis of AD |
Leng et al. 2020 [269] | 10× Genomics platform | Post-mortem brain tissues | GEO: GSE147528 | The study identified a subpopulation of reactive astrocytes characterized by reduced expression of genes involved in homeostasis |
Walgrave et al. 2021 [261] | 10× Genomics platform | Human hippocampal and serum samples | GEO: GSE172402 | The study revealed that miR-132 is one of the most consistently down-regulated miRNAs in AD and an effective regulator of adult hippocampal neurogenesis (AHN), and plays a cell-autonomic neurogenic role in adult neural stem cells and their progeny. AHN was shown to be directly affected by AD pathology. miR-132 replacement in the hippocampus of adult AD mice restored AHN and alleviated associated memory deficits |
Lee et al. 2021 [270] | Illumina HiSeq4000 platform | Hippocampus of AD mice model | Cohort I (GSE160512), cohort II (GSE181786) and cohort III (GSE153895) | The spatial distribution of two types of oligodendrocytes with distinct transcriptional states was revealed. TREM2-deficient animals exhibited drastically delayed microglial responses to tau and Aβ pathology, whereas non-microglial (oligodendrocytes, astrocytes and T cells) responses remained unaltered |
Freitag et al. 2022 [271] | 10× Genomics platform | Cerebral hemisphere of APP/PS1 mice | GEO: GSE206202 | The study identified a population of microglia characterized by elevated AXL levels and expression of phagocytosis- and cell-migration-related genes. Subsequent proteomic analysis of microglia isolated from APP/PS1 mice validated the anti-inflammatory and cytoskeletal effects of spermidine. Autophagy induced by spermidine altered the TLR3- and TLR4-mediated inflammatory processes, Aβ phagocytosis and motility in primary microglia and astrocytes |
Lampinen et al. 2022 [272] | Illumina NovaSeq S1 platform | Olefin mucosa cells extracted from three cognitively healthy individuals (mean age, 71.7 years) and five patients with AD (mean age, 67.2 years) | European Genome-phenome Archive (EGA, https://ega-archive.org/, 10 February 2022) under the accession ID EGAS00001006019 | Single-cell RNA sequencing revealed altered expression of mitochondrial localization-related genes in olefin mucosa cells in AD. This finding was corroborated by functional assays, which revealed altered mitochondrial respiration and decreased ATP generation |
Wood et al. 2022 [273] | Illumina NextSeq 2000 platform | Cerebral hemisphere of APPNL−F/NL−F knockin mice | All data reported in this study will be shared by the corresponding author upon request | The TREM2-dependent genes are all involved in phagocytosis and degradation. The decrease in phagocytosis markers is associated with an increase of tiny plaques in mice with TREM2 mutations. Furthermore, in the presence of R47H mutation that prevents the increase in TREM2 expression, there were still small increases in TREM2 protein and microglial density on plaques. The results indicate that the interaction between microglia and plaques and the activity of TREM2 are both required for microglia to respond appropriately to amyloid-related diseases |