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

Anna Podleśny-Drabiniok; Carmen Romero-Molina; Tulsi Patel; Wen Yi See; Yiyuan Liu; Edoardo Marcora; Alison M Goate

doi:10.1016/j.celrep.2025.115909

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

Cell Rep. 2025 Jun 25;44(7):115909. doi: 10.1016/j.celrep.2025.115909. Online ahead of print.

Authors

Anna Podleśny-Drabiniok¹, Carmen Romero-Molina¹, Tulsi Patel¹, Wen Yi See¹, Yiyuan Liu¹, Edoardo Marcora², Alison M Goate³

Affiliations

¹ Ronald M. Loeb Center for Alzheimer's Disease, Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029, USA.
² Ronald M. Loeb Center for Alzheimer's Disease, Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029, USA; Sanford Grossman Interdisciplinary Program In Neural Circuitry and Immune Function, New York, NY 10029, USA. Electronic address: edoardo.marcora@mssm.edu.
³ Ronald M. Loeb Center for Alzheimer's Disease, Department of Genetics & Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029, USA; Sanford Grossman Interdisciplinary Program In Neural Circuitry and Immune Function, New York, NY 10029, USA. Electronic address: alison.goate@mssm.edu.

PMID: 40570367
DOI: 10.1016/j.celrep.2025.115909

Abstract

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.

Keywords: Alzheimer’s disease; CP: Immunology; CP: Neuroscience; DAM; IL-4; LAM; THP-1 macrophages; disease-associated microglia; efferocytosis; lipid-associated macrophages.