Effects of autologous serum on TREM2 and APOE in a personalized monocyte-derived macrophage assay of late-onset Alzheimer’s patients

Immunity & Ageing

Research

Neriman Eren¹  Susanna Gerike¹  Berk Üsekes¹  Nicoleta-Carmen Cosma²  Julian Hellmann-Regen²  Oliver Peters³ 

[1] Department of Psychiatry and Psychotherapy, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Section Clinical Neurobiology, Campus Benjamin Franklin, Hindenburgdamm 30, 12203, Berlin, Germany;Department of Psychiatry and Psychotherapy, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Section Clinical Neurobiology, Campus Benjamin Franklin, Hindenburgdamm 30, 12203, Berlin, Germany;BIH Biomedical Innovation Academy, BIH Charité Clinician Scientist Program, Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany;Department of Psychiatry and Psychotherapy, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Section Clinical Neurobiology, Campus Benjamin Franklin, Hindenburgdamm 30, 12203, Berlin, Germany;German Center for Mental Health (DZPG) Partner Site Berlin, Berlin, Germany;

关键词: Late-onset Alzheimer's disease;    TREM2;    APOE;    Monocyte-derived macrophages;    Amyloid-beta uptake;    Sex differences;    Patient-derived personalized assay;    Inflammaging;   

DOI  :  10.1186/s12979-023-00376-2

 received in 2023-08-12, accepted in 2023-09-14,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundAge-associated deterioration of the immune system contributes to a chronic low-grade inflammatory state known as “inflammaging” and is implicated in the pathogenesis of late-onset Alzheimer's disease (LOAD). Whether changes in the tissue environment caused by circulatory factors associated with aging may alter the innate immune response is unknown. Monocyte-derived macrophages (Mo-MФs) infiltrating the brain alongside microglia are postulated to play a modulatory role in LOAD and both express triggering receptor expressed on myeloid cells 2 (TREM2). Apolipoprotein E (APOE) acts as a ligand for TREM2, and their role in amyloid beta (Aβ) clearance highlights their importance in LOAD. However, the influence of the patient's own milieu (autologous serum) on the synthesis of TREM2 and APOE in infiltrating macrophages remains unknown.ObjectivesTo functionally assess patient-specific TREM2 and APOE synthesis, we designed a personalized assay based on Mo-MФs using monocytes from LOAD patients and matched controls (CO). We assessed the influence of each participant’s own milieu, by examining the effect of short- (1 day) and long- (10 days) term differentiation of the cells in the presence of the donor´s autologous serum (AS) into M1-, M2- or M0-macrophages. Additionally, sex differences and Aβ-uptake ability in short- and long-term differentiated Mo-MФs were assessed.ResultsWe showed a time-dependent increase in TREM2 and APOE protein levels in LOAD- and CO-derived cells. While AS did not differentially modulate TREM2 compared to standard fetal calf serum (FCS), AS decreased APOE levels in M2 macrophages but increased levels in M1 macrophages. Interestingly, higher levels of TREM2 and lower levels of APOE were detected in female- than in male- LOAD patients. Finally, we report decreased Aβ-uptake in long-term differentiated CO- and LOAD-derived cells, particularly in APOEε4(+) carriers.ConclusionsWe demonstrate for the first time the suitability of a personalized Mo-MФ cell culture-based assay for studying functional TREM2 and APOE synthesis in a patient's own aged milieu. Our strategy may thus provide a useful tool for future research on diagnostic and therapeutic aspects of personalized medicine.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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