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Abstract

Introduction

Recent evidence increasingly supports a potential role of Perivascular Macrophages (PVMs), a unique subpopulation of brain immune cells, in the pathogenesis of Alzheimer’s disease (AD). Strategically positioned at the brain-vasculature interface, PVMs sense the redox status, modulate immunity, and potentially influence ferroptosis—an iron-dependent form of regulated cell death increasingly implicated in AD. However, whether the involvement of PVMs in AD pathology specifically entails mechanisms related to the crosstalk between immunometabolism and ferroptosis, and the precise molecular pathways linking PVMs, immunometabolism, and ferroptosis to AD, remains unclear.

Methods

We first obtained single-cell RNA sequencing data of PVMs from AD patients and control subjects the GEO database, identified Differentially Expressed Genes (DEGs), and applied Mendelian Randomization (MR), with robustness validated leave-one-out analysis to pinpoint key genes among the DEGs with causal relevance to AD. Next, we identified ferroptosis-related genes within these key genes and examined their associations with immune cell infiltration and immunometabolic signaling pathways, while also predicting their regulatory transcription factors to inform potential therapeutic strategies.

Results

We identified 149 DEGs in PVMs between AD and control groups, which were primarily enriched in immune and metabolic pathways. MR analysis established eight genes (, , , , , , , and ) as causally and negatively associated with AD risk (IVW analysis identified all < 0.05, with robustness confirmed by leave-one-out analysis), with being recognized as a known ferroptosis driver. Immune cell infiltration analysis revealed significant differences in monocyte and neutrophil proportions in AD, with identified as the sole gene significantly correlated with monocyte abundance. The Key genes demonstrated distinct associations with immunometabolic pathways: expression was positively associated with PI3K/AKT/mTOR signaling, whereas both and showed enrichment in cells with high Notch signaling activity. exhibited robust associations with multiple pathways implicated in ferroptosis, including the IL-6/JAK/STAT3, interferon-γ, TGF-β, bile acid metabolism, and cholesterol homeostasis pathways, suggesting potential mechanisms that mediate the crosstalk between immunometabolism and ferroptosis. Transcription factor analysis highlighted shared regulation by CEBPD and the SP1/2/3/4 family, indicating convergent transcriptional control of these genes.

Conclusion

This study identifies eight key genes in PVMs that may protect against AD through mechanisms involving the interplay between immunometabolism and ferroptosis. Our findings provide novel insights into the function of PVMs in AD pathophysiology and suggest potential therapeutic targets for this devastating neurodegenerative disease.

© 2025 The Author(s). Published by Bentham Science Publishers.
This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
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2025-09-18
2025-11-05

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/content/journals/cn/10.2174/011570159X417328250908080404
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Unraveling the Role of Perivascular Macrophages in Alzheimer's Disease: Insights from the Crosstalk between Immunometabolism and Ferroptosis
Bentham Science Publishers ; https://doi.org/10.2174/011570159X417328250908080404
/content/journals/cn/10.2174/011570159X417328250908080404
/content/journals/cn/10.2174/011570159X417328250908080404
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  • Article Type:     Research Article
Keywords: ferroptosis ; immune infiltration ; single-cell RNA sequencing ; mendelian randomization ; perivascular macrophages ; Alzheimer’s disease

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