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| Status |
Public on Dec 30, 2023 |
| Title |
Amyloid driven clonally expanded CD8+ effector memory T cells infiltrate Alzheimer’s disease bigenic mouse models |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Other
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| Summary |
Alzheimer’s Disease (AD) is the most common cause of age-related dementia and the sixth leading cause of death in the United States. AD neuropathology is primarily characterized by the accumulation of extracellular beta-amyloid (Aβ) plaques and intraneuronal neurofibrillary tau tangles. In addition to these hallmark AD pathologies, many other important pathological changes occur in the brains of AD patients, including synaptic and neuronal loss and neuroinflammation. Most recently, genome-wide association studies (GWAS) have provided substantial new evidence that immune dysfunction may contribute to the development and progression of AD. To date over 60 GWAS loci have been identified and almost two thirds of these genes are highly expressed in microglia, the resident innate immune cell of the brain. These genetic discoveries have in turn inspired many new studies of microglial biology and the role of these cells in AD. In contrast, the role of the adaptive immunity in AD remains understudied, despite evidence that many of AD risk genes are also highly expressed in T and B cells. To investigate the role of T cell infiltration in AD, we examined T cells from immune-deficient AD mice via bone marrow transplantation studies using flow cytometry and immunohistochemistry; and from immune-intact transgenic AD model mice using flow cytometry, immunohistochemistry, and single-cell RNA sequencing. Our experiments demonstrate that multiple T cell subtypes infiltrate the AD brain, and that effector memory CD8 T cells are specifically enriched in response to Aβ pathology or a combination of Aβ and tau pathologies. Single-cell sequencing analysis revealed high expression of over 40 AD risk genes between several T cell sub-populations, implying a need for more research of these T cell phenotypes in AD development. Additionally, T-cell receptor (TCR) sequencing revealed increased clonal expansion of T cells from mice that developed Aβ pathology or Aβ and tau pathology, suggesting amyloid-driven recruitment and clonal expansion of T cells in these mice. Ultimately, this study demonstrates the crucial importance of investigating the role of T cells in AD and provides a guide for future experiments to continue to enhance our understanding of AD immunology.
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| Overall design |
Single cell RNA and TCR sequencing of T cells from the brains of 9-month-old female WT, 5XFAD, PS19, and PS-5X mice. Each sample contains a pool of T cells from multiple mice of the same sex and genotype. The WT and 5XFAD genotypes have 2 samples (2 separate pools) and the PS19 and PS-5X genotypes have 1 sample (1 pool).
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| Contributor(s) |
Sanchez JR, Beck JR, Kiani Shabestari S, Marsh SE, McIntyre LL, Scarfone VM, Nguyen PU, Varady ES, Silva J, Claes C, Capocchi J, Chadarevian J, Lahian A, Inlay M, Walsh CM, Davtyan H, Blurton-Jones M |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
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| Submission date |
Sep 04, 2022 |
| Last update date |
Dec 30, 2023 |
| Contact name |
Mathew Blurton-Jones |
| E-mail(s) |
mblurton@uci.edu
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| Organization name |
University of California, Irvine
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| Street address |
Gross Hall, 845 Health Sciences Rd
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| City |
Irvine |
| State/province |
CA |
| ZIP/Postal code |
92617 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (12)
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| GSM6543232 |
5XFAD, RNA, rep2 |
| GSM6543233 |
PS19, RNA |
| GSM6543234 |
PS-5X, RNA |
| GSM6543235 |
WT, TCR, rep1 |
| GSM6543236 |
WT, TCR, rep2 |
| GSM6543237 |
5XFAD, TCR, rep1 |
| GSM6543238 |
5XFAD, TCR, rep2 |
| GSM6543239 |
PS19, TCR |
| GSM6543240 |
PS-5X, TCR |
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| Relations |
| BioProject |
PRJNA876731 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE212680_barcodes.tsv.gz |
93.5 Kb |
(ftp)(http) |
TSV |
| GSE212680_clonotypes.csv.gz |
284.4 Kb |
(ftp)(http) |
CSV |
| GSE212680_consensus_annotations.csv.gz |
1.9 Mb |
(ftp)(http) |
CSV |
| GSE212680_features.tsv.gz |
284.1 Kb |
(ftp)(http) |
TSV |
| GSE212680_filtered_contig_annotations.csv.gz |
2.8 Mb |
(ftp)(http) |
CSV |
| GSE212680_matrix.mtx.gz |
142.4 Mb |
(ftp)(http) |
MTX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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