ADAR Dysfunction in Brain Aging and Alzheimer's Disease

Abstract

Neuroinflammation is a central mechanism of brain aging and neurodegenerative disease, but why neuroinflammation develops with aging is incompletely understood. Adenosine deaminase RNA specific (ADAR) proteins are potential suppressors of neuroinflammation through their adenosine‐to‐inosine (A‐to‐I) editing and subsequent inhibition of double‐stranded RNA (dsRNA, an innate immune activator). However, the role of ADARs in brain aging and/or neurodegenerative disease (e.g., Alzheimer’s disease, AD) is unclear. To address this, we looked for age‐related changes in ADAR expression and function (indicated by A‐to‐I editing) in multiple, brain‐specific transcriptomic datasets. We found evidence of age‐related declines in ADAR expression in: 1) astrocytes (glial cells linked with immune/inflammatory signaling in aging and AD) in old vs. young mice; 2) induced astrocytes from old vs. young human subjects; and 3) brain tissue of AD patients vs. healthy age‐matched controls. We also found declines in A‐to‐I editing related to reduced ADAR expression, suggesting that ADAR and ADAR activity decline with age and disease. We followed up on these observations via in vitro experiments in primary human astrocytes, in which we suppressed ADAR via siRNA knockdown or with an ADAR inhibitor (8‐Azaadenosine). These treatments increased levels of the proinflammatory cytokine interleukin 6 (IL‐6) and intercellular adhesion molecule 1 (ICAM‐1, a marker of pro‐inflammatory astrocytes), and this was associated with accumulation/changes in the cellular distribution of dsRNA (assessed via immunofluorescence). Preliminary data showed that ADAR knockdown tended to increased levels of protein kinase R (PKR, a key pro‐inflammatory dsRNA sensor), and that dsRNA colocalizes with PKR. To identify related mechanisms, we are currently performing RNA‐seq to profile whole‐transcriptome changes associated with ADAR inhibition in astrocytes. Taken together, our data suggest that ADAR may be an important modulator of neuroinflammation in aging, and ultimately neurodegenerative diseases.