USP4-stabilized IRF1 is a key regulator of disease-associated microglial responses in Alzheimer’s disease
Year: 2026
Type: article
Abstract: Background Microglial dysfunction is a hallmark of Alzheimer’s disease (AD) pathology. Although interferon regulatory factor 1 (IRF1) is traditionally considered a pro-inflammatory factor, its role in regulating microglial function in AD remains poorly understood. Methods To investigate the role of IRF1 in AD, we generated microglia-specific IRF1 conditional knockout (cKO) mice on the FAD 4T amyloid mouse background. Behavioral assessment, immunofluorescence, flow cytometry, and SMART-seq II-based ribonucleic acid (RNA) sequencing were performed to evaluate disease progression and microglial phenotypes. In addition, luciferase reporter assays and ubiquitination analyses were employed to investigate the molecular mechanisms upstream and downstream of IRF1. Results IRF1 expression was markedly increased in amyloid-β (Aβ)-associated microglia. Conditional deletion of IRF1 in microglia significantly exacerbated amyloid plaque burden and cognitive deficits in FAD 4T mice, accompanied by attenuated microglial activation, impaired Aβ uptake, and broadly altered microglial transcriptional profiles. Mechanistically, IRF1 directly promoted Tyrobp transcription, and TYROBP re-expression partially restored Aβ phagocytosis in IRF1-deficient primary microglia. In addition, ubiquitin-specific protease 4 (USP4) interacted with IRF1 and stabilized IRF1 protein by removing K48-linked polyubiquitin chains. Conclusion Our findings identify IRF1 as an important regulator of microglial function during AD-associated amyloid pathology, with USP4 regulating its protein stability and TYROBP contributing to IRF1-mediated effects on Aβ uptake in vitro . These findings provide new insight into the molecular mechanisms underlying microglial responses in AD and offer a molecular framework for future studies aimed at modulating microglial function in neurodegenerative disease.
Source: Frontiers in Aging Neuroscience
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7225984425