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Proliferating Microglia Exhibit Unique Transcriptional and Functional Alterations in Alzheimer's Disease
Nàdia Villacampa1, Heela Sarlus1, Paula Martorell2
1Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany.
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.
Insights
Microglia proliferation in Alzheimer disease (AD) impairs their ability to clear beta-amyloid. Newly proliferated microglia exhibit altered functions and unique gene expression patterns, suggesting a novel role for proliferation in AD progression.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglia proliferation is accelerated in neurodegenerative disorders like Alzheimer disease (AD).
- The functional consequences of this accelerated microglial proliferation on disease progression remain largely unknown.
Purpose of the Study:
- To investigate the functional impact of microglia proliferation in Alzheimer disease.
- To identify molecular signatures associated with proliferating microglia in the context of AD.
Main Methods:
- Proliferating microglia were sorted from APP/PS1 transgenic mice models of AD.
- Transcriptome analysis was performed on sorted microglia.
- The role of DEAD-Box Helicase 3 X-Linked (DDX3X) in microglia function was investigated.
Main Results:
- Newly proliferated microglia demonstrated impaired beta-amyloid clearance in vivo.
- Unique, age- and beta-amyloid-dependent transcriptomic signatures were identified in proliferating microglia, enriched in immune pathways.
- DEAD-Box Helicase 3 X-Linked (DDX3X) was identified as a key regulator of microglia activation and cytokine secretion, and is present in the AD brain.
Conclusions:
- Microglia proliferation leads to significant alterations in cellular function, including impaired beta-amyloid clearance.
- Longitudinal phenotypic and functional changes in microglia occur in response to accelerated proliferation within the neurodegenerative environment.
- DDX3X emerges as a critical molecule influencing microglia behavior in AD.
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