Identification of Peripheral Blood GZMK+ CD8+ T Cells As Biomarkers of Alzheimer's Disease Based on Single-Cell Transcriptome

DUAN Tingting, CHU Jinyu, HU Feifei

Abstract

Based on single-cell RNA sequencing (scRNA-seq) to explore immune characteristics in the peripheral blood of patients with Alzheimer's disease (AD) as biomarkers.  Methods  GSE168522, the scRNA-seq dataset of AD peripheral blood immune cells, was downloaded from the Gene Expression Omnibus (GEO) database and was analyzed in the RAD-Blood web server (http://www.bioinform.cn/RAD-Blood/). The changes in blood cell composition in AD patients were analyzed. The abnormal communications between different types of cells in AD patients were investigated by the CellChat R package.   Results  There were two kinds of CD8+ T cells in the blood of AD patients and healthy individuals, one of which highly expressed granzyme K (GZMK) (false discovery rate [FDR]<0.05), and the other highly expressed GZMA, GZMB, and GZMH (FDR<0.05). In the blood of AD patients, the content of GZMK+ CD8+ T cells was increased by 32.9% (P=5.15E-21), their interactions with other cell types were increased, and they might be associated with AD through the abnormal signal transduction of major histocompatibility complex class Ⅰ (MHC-Ⅰ). Erythrocyte provided the main ligands, that are, human leukocyte antigen (HLA) class Ⅰ molecules, including HLA-A, HLA-B, HLA-C, and HLA-E, for the abnormal MHC-Ⅰ signaling pathway of GZMK+ CD8+ T cells. The RESISTIN signaling pathway was specifically enriched in the blood of AD patients.  Conclusion  The increased content of peripheral blood GZMK+ CD8+ T cells, the increased interaction between GZMK+ CD8+ T cells and erythrocytes, and the enhanced RESISTIN pathway are potential blood biomarkers of AD.


Key words: Alzheimer's disease, scRNA-seq, Blood biomarkers, CD8+ T cell

 

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References


2023 Alzheimer's disease facts and figures. Alzheimers Dement，2023， 19(4): 1598–1695. doi: 10.1002/alz.13016.

CHEN S H， TIAN D Y， SHEN Y Y， et al. Amyloid-beta uptake by blood monocytes is reduced with ageing and Alzheimer's disease. Transl Psychiatry，2020，10(1): 423. doi: 10.1038/s41398-020-01113-9.

YAN P， KIM K W， XIAO Q， et al. Peripheral monocyte-derived cells counter amyloid plaque pathogenesis in a mouse model of Alzheimer's disease. J Clin Invest，2022，132(11): e152565. doi: 10.1172/JCI152565.

ZENARO E， PIETRONIGRO E， DELLA BIANCA V， et al. Neutrophils promote Alzheimer's disease-like pathology and cognitive decline via LFA-1 integrin. Nat Med，2015，21(8): 880–886. doi: 10.1038/nm.3913.

UNGER M S， LI E， SCHARNAGL L， et al. CD8+ T-cells infiltrate Alzheimer's disease brains and regulate neuronal- and synapse-related gene expression in APP-PS1 transgenic mice. Brain Behav Immun，2020， 89: 67–86. doi: 10.1016/j.bbi.2020.05.070.

XIONG L L， XUE L L， DU R L， et al. Single-cell RNA sequencing reveals B cell-related molecular biomarkers for Alzheimer's disease. Exp Mol Med，2021，53(12): 1888–1901. doi: 10.1038/s12276-021-00714-8.

BOLGER A M， LOHSE M， USADEL B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics，2014，30(15): 2114–2120. doi: 10.1093/bioinformatics/btu170.

BUTLER A， HOFFMAN P， SMIBERT P， et al. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol，2018，36(5): 411–420. doi: 10.1038/nbt.4096.

HAO Y， HAO S， ANDERSEN-NISSEN E， et al. Integrated analysis of multimodal single-cell data. Cell，2021，184(13): 3573–3587.e29. doi: 10. 1016/j.cell.2021.04.048.

OBERSTEIN T J， TAHA L， SPITZER P， et al. Imbalance of circulating Th17 and regulatory T cells in Alzheimer's disease: a case control study. Front Immunol，2018，9: 1213. doi: 10.3389/fimmu.2018.01213.

FU J， DUAN J， MO J， et al. Mild cognitive impairment patients have higher regulatory T-cell proportions compared with Alzheimer’s disease-related dementia patients. Front Aging Neurosci，2021，12: 624304. doi: 10.3389/fnagi.2020.624304.

HUANG L T， ZHANG C P， WANG Y B， et al. Association of peripheral blood cell profile with Alzheimer's disease: a meta-analysis. Front Aging Neurosci，2022，14: 888946. doi: 10.3389/fnagi.2022.888946.

XU H， JIA J. Single-cell RNA sequencing of peripheral blood reveals immune cell signatures in Alzheimer's disease. Front Immunol，2021，12: 645666. doi: 10.3389/fimmu.2021.645666.

LI J， ZHANG Y， LU T， et al. Identification of diagnostic genes for both Alzheimer's disease and Metabolic syndrome by the machine learning algorithm. Front Immunol，2022，13: 1037318. doi: 10.3389/fimmu.2022. 1037318.

GATE D， SALIGRAMA N， LEVENTHAL O， et al. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease. Nature， 2020，577(7790): 399–404. doi: 10.1038/s41586-019-1895-7.

JONSSON A H， ZHANG F， DUNLAP G， et al. Granzyme K+ CD8 T cells form a core population in inflamed human tissue. Sci Transl Med， 2022，14(649): eabo0686. doi: 10.1126/scitranslmed.abo0686.

ISMAIL R， PARBO P， MADSEN L S， et al. The relationships between neuroinflammation, beta-amyloid and tau deposition in Alzheimer's disease: a longitudinal PET study. J Neuroinflammation，2020，17(1): 151. doi: 10.1186/s12974-020-01820-6.

KIZILARSLANOĞLU M C， KARA Ö， YEŞIL Y， et al. Alzheimer disease, inflammation, and novel inflammatory marker: resistin. Turk J Med Sci，2015，45(5): 1040–1046.


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