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Proliferating Microglia Exhibit Unique Transcriptional and Functional Alterations in Alzheimer’s Disease
Villacampa, Nadia Sarlus, Heela Martorell, Paula Bhalla, Khushbu Castro-Gomez, Sergio Vieira-Saecker, Ana Slutzkin, Ilya Handler, Kristian Venegas, Carmen McManus, Roisin
Villacampa, Nadia
Sarlus, Heela
Martorell, Paula
Bhalla, Khushbu
Castro-Gomez, Sergio
Vieira-Saecker, Ana
Slutzkin, Ilya
Handler, Kristian
Venegas, Carmen
McManus, Roisin
Supervisor
Department
Computational Biology
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Type
Journal article
Date
2025
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Language
English
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Abstract
Proliferation of microglia represents a physiological process, which is accelerated in several neurodegenerative disorders including Alzheimer disease (AD). The effect of such neurodegeneration-associated microglial proliferation on function and disease progression remains unclear. Here, we show that proliferation results in profound alterations of cellular function by providing evidence that newly proliferated microglia show impaired beta-amyloid clearance in vivo. Through sorting of proliferating microglia of APP/PS1 mice and subsequent transcriptome analysis, we define unique proliferation-associated transcriptomic signatures that change with age and beta-amyloid accumulation and are characterized by enrichment of immune system-related pathways. Of note, we identify the DEAD-Box Helicase 3 X-Linked (DDX3X) as a key molecule to modulate microglia activation and cytokine secretion and it is expressed in the AD brain. Together, these results argue for a novel concept by which phenotypic and functional microglial changes occur longitudinally as a response to accelerated proliferation in a neurodegenerative environment.
Citation
N. Villacampa et al., “Proliferating Microglia Exhibit Unique Transcriptional and Functional Alterations in Alzheimer’s Disease,” ASN Neuro , vol. 17, no. 1, Dec. 2025, doi: 10.1080/17590914.2025.2506406
Source
ASN neuro
Conference
Keywords
Alzheimer’s disease, Inflammasome, Microglia, Aproliferation, Transcriptome
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Publisher
Taylor & Francis