ADAR1 suppression causes interferon signaling and transposable element transcript accumulation in human astrocytes

Area of Science:

• Neuroscience
• Immunology
• Genetics

Background:

• Neuroinflammation is a key factor in brain aging and Alzheimer's disease (AD).
• Adenosine deaminase acting on RNA 1 (ADAR1) regulates endogenous double-stranded RNA (dsRNA), a trigger for inflammatory responses.
• The specific function of ADAR1 in astrocytes, crucial for neuroinflammation, remains unclear.

Purpose of the Study:

• To investigate the role of ADAR1 in modulating astrocyte inflammatory responses.
• To identify ADAR1's transcriptomic targets within astrocytes.
• To assess the clinical relevance of ADAR1 in aging and AD.

Main Methods:

• Primary human astrocytes were treated with siRNA to reduce ADAR1 expression.
• Transcriptomic analysis (RNA-seq) was performed to assess gene expression changes.
• ADAR1 gene expression and transposable element (TE) transcript levels were analyzed in human brain aging and AD cohorts.

Main Results:

• Knocking down ADAR1 in astrocytes increased type I interferon and pro-inflammatory signaling pathways.
• ADAR1 depletion led to the accumulation of transposable element (TE) transcripts capable of forming dsRNA.
• Reduced ADAR1 expression correlated with increased TE transcripts in human brain aging and AD.

Conclusions:

• ADAR1 plays a critical role in suppressing pro-inflammatory activation of astrocytes.
• ADAR1 mitigates inflammation by controlling endogenous dsRNA, particularly dsRNA derived from TEs.
• Dysregulation of ADAR1 contributes to neuroinflammation in aging and Alzheimer's disease.