APOE ε4–associated downregulation of the IL‐7/IL‐7R pathway in effector memory T cells: Implications for Alzheimer's disease

Author:

Zhang Ying‐Jie12,Cheng Yan34,Tang Hai‐Liang5,Yue Qi5,Cai Xin‐Yi6,Lu Zhi‐Jie1,Hao Yi‐Xuan1,Dai An‐Xiang1,Hou Ting1,Liu Hao‐Xin1,Kong Nan1,Ji Xiao‐Yu1,Lu Chang‐Hao1,Xu Sheng‐Liang1,Huang Kai3,Zeng Xin7,Wen Ya‐Qi3,Ma Wan‐Yin3,Guan Ji‐Tian3,Lin Yan3,Zheng Wen‐Bin3,Pan Hui8,Wu Jie1,Wu Ren‐Hua3,Wei Nai‐Li1ORCID

Affiliation:

1. Department of Neurosurgery The First Affiliated Hospital of Shantou University Medical College Shantou China

2. Department of Rehabilitation The First Affiliated Hospital of Shantou University Medical College Shantou China

3. Department of Radiology The Second Affiliated Hospital of Shantou University Medical College Shantou China

4. Department of Radiology The Second Hospital of Shandong University Jinan China

5. Department of Neurosurgery Fudan University Huashan Hospital Shanghai Medical College Fudan University Shanghai China

6. Department of Pathology Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology Shantou University Medical College Shantou China

7. Department of Geriatrics The First Affiliated Hospital of Shantou University Medical College Shantou China

8. Department of Family Medicine Shantou Longhu People's Hospital Shantou China

Abstract

AbstractINTRODUCTIONThe apolipoprotein E (APOE) ε4 allele exerts a significant influence on peripheral inflammation and neuroinflammation, yet the underlying mechanisms remain elusive.METHODSThe present study enrolled 54 patients diagnosed with late‐onset Alzheimer's disease (AD; including 28 APOE ε4 carriers and 26 non‐carriers). Plasma inflammatory cytokine concentration was assessed, alongside bulk RNA sequencing (RNA‐seq) and single‐cell RNA sequencing (scRNA‐seq) analysis of peripheral blood mononuclear cells (PBMCs).RESULTSPlasma tumor necrosis factor α, interferon γ, and interleukin (IL)‐33 levels increased in the APOE ε4 carriers but IL‐7 expression notably decreased. A negative correlation was observed between plasma IL‐7 level and the hippocampal atrophy degree. Additionally, the expression of IL‐7R and CD28 also decreased in PBMCs of APOE ε4 carriers. ScRNA‐seq data results indicated that the changes were mainly related to the CD4+ Tem (effector memory) and CD8+ Tem T cells.DISCUSSIONThese findings shed light on the role of the downregulated IL‐7/IL‐7R pathway associated with the APOE ε4 allele in modulating neuroinflammation and hippocampal atrophy.Highlights The apolipoprotein E (APOE) ε4 allele decreases plasma interleukin (IL)‐7 and aggravates hippocampal atrophy in Alzheimer's disease. Plasma IL‐7 level is negatively associated with the degree of hippocampal atrophy. The expression of IL‐7R signaling decreased in peripheral blood mononuclear cells of APOE ε4 carriers Dysregulation of the IL‐7/IL‐7R signal pathways enriches T cells.

Funder

National Natural Science Foundation of China

Natural Science Foundation of Guangdong Province

Publisher

Wiley

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