Abstract
The peripheral immune system in Alzheimer's disease (AD) has not been thoroughly studied with modern sequencing methods. To investigate epigenetic and transcriptional alterations to the AD peripheral immune system, we used single-cell sequencing strategies, including assay for transposase-accessible chromatin and RNA sequencing. We reveal a striking amount of open chromatin in peripheral immune cells in AD. In CD8 T cells, we uncover a cis-regulatory DNA element co-accessible with the CXC motif chemokine receptor 3 gene promoter. In monocytes, we identify a novel AD-specific RELA transcription factor binding site adjacent to an open chromatin region in the nuclear factor kappa B subunit 2 gene. We also demonstrate apolipoprotein E genotype-dependent epigenetic changes in monocytes. Surprisingly, we also identify differentially accessible chromatin regions in genes associated with sporadic AD risk. Our findings provide novel insights into the complex relationship between epigenetics and genetic risk factors in AD peripheral immunity.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1235-1248.e5 |
| Journal | Neuron |
| Volume | 112 |
| Issue number | 8 |
| DOIs | |
| State | Published - Apr 17 2024 |
Funding
We thank the clinical staff members of the Stanford Alzheimer's Disease Research Center (ADRC) for their assistance in acquiring patient samples. We thank Ted Wilson (Stanford University) for providing biomarker data. We also thank Divya Channappa, Tony Wyss-Coray, and Victor Henderson (Stanford University) for providing PBMC samples under Stanford P30AG066515. Some figures were created using BioRender.com. This work was supported by a National Institute of Neurologic Disease and Stroke K99/R00 Pathway to Independence award NS112458-01A1 (D.G.), an NIA R01AG078713-01 (D.G.), the Cure Alzheimer's Fund (D.G.), Alzheimer's Association 23AARG-1026607 (D.G.), Bright Focus Foundation A2023003S (D.G.), and a pilot project through the Northwestern University ADRC 1P30AG072977-01 (D.G.). A.R. performed scATAC-seq, conducted bioinformatics analysis, and designed figures. N.P. performed bioinformatics analysis and generated figures. B.S. and V.T. performed sequencing library preparation. M.P. and Z.Z. assisted with bioinformatics analysis. L.v.O. assisted with study design. D.G. performed scRNA-seq, conceptualized and led the study, and wrote the manuscript. All authors read and approved the final manuscript. D.G. is an inventor on a patent related to this work. Patent US-2022-0170908-A1 is for compositions and methods for measuring T cell markers associated with AD. We thank the clinical staff members of the Stanford Alzheimer\u2019s Disease Research Center (ADRC) for their assistance in acquiring patient samples. We thank Ted Wilson (Stanford University) for providing biomarker data. We also thank Divya Channappa, Tony Wyss-Coray, and Victor Henderson (Stanford University) for providing PBMC samples under Stanford P30AG066515. Some figures were created using BioRender.com . This work was supported by a National Institute of Neurologic Disease and Stroke K99/R00 Pathway to Independence award NS112458-01A1 (D.G.), an NIA R01AG078713-01 (D.G.), the Cure Alzheimer\u2019s Fund (D.G.), Alzheimer\u2019s Association 23AARG-1026607 (D.G.), Bright Focus Foundation A2023003S (D.G.), and a pilot project through the Northwestern University ADRC 1P30AG072977-01 (D.G.).
Keywords
- Alzheimer's disease
- T cells
- bioinformatics
- chromatin
- epigenetics
- immunity
- monocytes
- single-cell ATAC-seq
- single-cell RNA sequencing
- transcriptomics
ASJC Scopus subject areas
- General Neuroscience