Cytokine-induced reprogramming of human macrophages toward Alzheimer’s disease-relevant molecular and cellular phenotypes in vitro

Cytokine-induced reprogramming of human macrophages toward Alzheimer’s disease-relevant molecular and cellular phenotypes in vitro

Summary: Myeloid cells, including brain-resident microglia and peripheral macrophages, play key roles in neurodegenerative diseases such as Alzheimer’s disease (AD). Studying their disease-associated states is limited by the lack of robust in vitro models. Here, we test whether a cytokine mix (inter...

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Bibliographic Details
Main Authors: Anna Podleśny-Drabiniok, Carmen Romero-Molina, Tulsi Patel, Wen Yi See, Yiyuan Liu, Edoardo Marcora, Alison M. Goate
Format: Article
Language:English
Published: Elsevier 2025-07-01
Series:Cell Reports
Subjects:
CP: Neuroscience
CP: Immunology
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124725006801
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Summary:Summary: Myeloid cells, including brain-resident microglia and peripheral macrophages, play key roles in neurodegenerative diseases such as Alzheimer’s disease (AD). Studying their disease-associated states is limited by the lack of robust in vitro models. Here, we test whether a cytokine mix (interleukin [IL]-4, CSF1, IL-34, and transforming growth factor-β) reprograms human THP-1 macrophages toward AD-relevant phenotypes. This treatment induces significant transcriptomic changes, driving THP-1 macrophages toward a transcriptional state reminiscent of disease-associated microglia and lipid-associated macrophages (LAM), collectively referred to as DLAM. Transcriptome profiling reveals gene expression changes related to oxidative phosphorylation, lysosome function, and lipid metabolism. Single-cell RNA sequencing shows an increased proportion of DLAM clusters in cytokine mix-treated THP-1 macrophages. Functional assays demonstrate alterations in cell motility, phagocytosis, lysosomal activity, and metabolic profiles. These findings provide insights into cytokine-mediated reprogramming of macrophages toward disease-relevant states, highlighting their role in neurodegenerative diseases and potential for therapeutic development.
ISSN:2211-1247

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