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Published on: June 14, 2020
Basic Science and Pathogenesis
1Columbia University, New York, NY, USA; Taub Institute, New York, NY, USA.
Background:
Microglia, the brain's resident immune cells, play a critical role in the pathogenesis of late-onset Alzheimer's disease (LOAD). Recent evidence suggests that transposable elements such as long interspersed nuclear element-1 (LINE-1) may contribute to neuroinflammation and cellular dysfunction in LOAD. However, the specific role of LINE-1 in microglial dysfunction and its contribution to disease pathogenesis remain poorly understood.
Methods:
We investigated LINE-1 expression in neurons, astrocytes, oligodendrocytes, and microglia using postmortem prefrontal cortex tissue from individuals with LOAD and age-matched cognitively normal controls. Immunoreactivity of the LINE-1-encoded open reading frame 1 protein (ORF1p) was quantified in microglia, and correlations with disease-associated morphology were assessed. In vitro, human iPSC-derived microglia (iMG) were used to model LINE-1 activation via CRISPR-mediated transcriptional activation. Microglial morphology, cytokine secretion, amyloid beta (Aβ) phagocytosis, and transcriptomic changes were analyzed.
Results:
We observed elevated ORF1p immunoreactivity in microglia from LOAD patients compared to controls, correlating with disease-associated microglial morphology. In iMG, CRISPR-mediated LINE-1 activation induced morphological changes, altered cytokine secretion, and impaired Aβ phagocytosis. Transcriptomic analyses revealed that LINE-1 activation affected genes involved in antigen presentation, lipid metabolism, and multiple Alzheimer's disease-relevant pathways.
Conclusions:
Our findings suggest that LINE-1 activation drives microglial dysregulation, contributing to neuroinflammation and cellular dysfunction in LOAD. These data identify LINE-1 as a novel mechanism of microglial impairment and position it as a potential therapeutic target for mitigating neuroinflammatory processes in Alzheimer's disease.
Insights
LINE-1 activation in microglia contributes to neuroinflammation and dysfunction in late-onset Alzheimer's disease (LOAD). This study identifies LINE-1 as a key factor in microglial impairment and a potential therapeutic target for Alzheimer's disease.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglia are crucial immune cells in the brain, implicated in late-onset Alzheimer's disease (LOAD) pathogenesis.
- Transposable elements, specifically long interspersed nuclear element-1 (LINE-1), are suspected contributors to neuroinflammation in LOAD.
- The precise role of LINE-1 in microglial dysfunction and its impact on Alzheimer's disease progression are not well understood.
Purpose of the Study:
- To investigate the role of LINE-1 expression and activation in microglial dysfunction within the context of LOAD.
- To determine if LINE-1 activation directly impacts microglial function, including morphology, phagocytosis, and inflammatory responses.
- To identify LINE-1 as a potential therapeutic target for LOAD.
Main Methods:
- Examined LINE-1-encoded open reading frame 1 protein (ORF1p) in postmortem brain tissue from LOAD patients and controls.
- Quantified ORF1p in microglia and correlated it with disease-associated morphology.
- Utilized human induced pluripotent stem cell-derived microglia (iMG) to model LINE-1 activation using CRISPR technology.
- Assessed microglial morphology, cytokine secretion, amyloid-beta (Aβ) phagocytosis, and transcriptomic changes in response to LINE-1 activation.
Main Results:
- Elevated ORF1p levels were found in microglia of LOAD patients, correlating with altered microglial morphology.
- Experimental LINE-1 activation in iMG led to morphological changes, increased pro-inflammatory cytokine secretion, and impaired Aβ phagocytosis.
- Transcriptomic analysis revealed that LINE-1 activation modulated genes involved in antigen presentation, lipid metabolism, and AD-related pathways.
Conclusions:
- LINE-1 activation is a significant driver of microglial dysregulation, exacerbating neuroinflammation and cellular dysfunction in LOAD.
- This research highlights LINE-1 as a novel mechanism underlying microglial impairment in Alzheimer's disease.
- LINE-1 presents a promising therapeutic target for modulating neuroinflammation and potentially treating LOAD.
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