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| Status |
Public on Apr 26, 2024 |
| Title |
Characterization of premature cell senescence in Alzheimer’s disease using single nuclear transcriptomics |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Aging is associated with cell senescence and is the major risk factor for AD. We characterized premature cell senescence in post mortem brains from non-diseased controls (NDC) and donors with Alzheimer’s disease (AD) using imaging mass cytometry (IMC) and single nuclear RNA (snRNA) sequencing (>200,000 nuclei). We found increases in numbers of glia immunostaining for galactosidase beta (>4-fold) and p16INK4A (up to 2-fold) with AD relative to NDC. Increased glial expression of genes related to senescence was associated with greater -amyloid load. Prematurely senescent microglia downregulated phagocytic pathways suggesting reduced capacity for -amyloid clearance. Gene set enrichment and pseudo-time trajectories described extensive DNA double-strand breaks (DSBs), mitochondrial dysfunction and ER stress associated with increased β-amyloid leading to premature senescence in microglia. We replicated these observations with independent AD snRNA-seq datasets. Our results describe a burden of senescent glia with AD that is sufficiently high to contribute to disease progression. These findings support the hypothesis that microglia are a primary target for senolytic treatments in AD.
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| Overall design |
This study was carried out in accordance with the Regional Ethics Committee and Imperial College Use of Human Tissue guidelines. Cases were selected based first on neuropathological diagnosis from UK brain banks (London Neurodegeneration [King’s College London] and Parkinson’s UK [Imperial College London] Brain Bank). We then excluded cases with clinical or pathological evidence for small vessel disease, stroke, cerebral amyloid angiopathy, diabetes, Lewy body pathology (TDP-43), or other neurological diseases. Where the information was available, cases were selected with a post-mortem delay of less than 60 h. Samples included EC, MTG and SSC cortices from a final set of 17 cases including 8 NDC donors (Braak stage 0–II) and 9 neuropathologically defined AD (Braak stage III–VI) donors (total of 49 brain samples).
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Submitter states that missing raw files are due to patient privacy concerns.
For raw files, visit the project space in https://www.synapse.org/#!Synapse:syn36812517/wiki/619350
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| Contributor(s) |
Fancy N, Smith AM, Caramello A, Tsartsalis S, Davey K, Muirhead RC, McGarry A, Jenkins M, Schneegans E, Chau V, Thomas M, Boulger S, Cheung TK, Adair E, Papageorgopoulou M, Willumsen N, Khozoie C, Gomez-Nicola D, Jackson J, Matthews PM |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Apr 23, 2024 |
| Last update date |
Apr 26, 2024 |
| Contact name |
Paul M Matthews |
| E-mail(s) |
[email protected]
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| Organization name |
Imperial College London
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| Street address |
White City
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| City |
London |
| ZIP/Postal code |
W12 0NN |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
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| Samples (49)
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| Relations |
| BioProject |
PRJNA1103739 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE264648_UMAP_Liger_all_celltype.rds.gz |
2.9 Mb |
(ftp)(http) |
RDS |
| GSE264648_UMAP_astrocytes.rds.gz |
447.7 Kb |
(ftp)(http) |
RDS |
| GSE264648_UMAP_microglia.rds.gz |
198.3 Kb |
(ftp)(http) |
RDS |
| GSE264648_UMAP_oligodendrocytes.rds.gz |
768.0 Kb |
(ftp)(http) |
RDS |
| GSE264648_counts_all_celltype.rds.gz |
1.4 Gb |
(ftp)(http) |
RDS |
| GSE264648_counts_astrocytes.rds.gz |
132.7 Mb |
(ftp)(http) |
RDS |
| GSE264648_counts_microglia.rds.gz |
42.5 Mb |
(ftp)(http) |
RDS |
| GSE264648_counts_oligodendrocytes.rds.gz |
198.1 Mb |
(ftp)(http) |
RDS |
| GSE264648_metadata_all_celltype.rds.gz |
8.0 Mb |
(ftp)(http) |
RDS |
| GSE264648_metadata_astrocytes.rds.gz |
2.1 Mb |
(ftp)(http) |
RDS |
| GSE264648_metadata_microglia.rds.gz |
1.5 Mb |
(ftp)(http) |
RDS |
| GSE264648_metadata_oligodendrocytes.rds.gz |
6.0 Mb |
(ftp)(http) |
RDS |
| Raw data not provided for this record |
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