Alzheimer's disease (AD) is sexually dimorphic in prevalence, progression, and severity. Yet, the mechanistic basis of this divergence, particularly the neuroinflammation phenotype evidently associated with AD, remains poorly characterised. Recent evidence suggests fundamental differences in genomic instability between females and males. Z-DNA, the left-handed conformation of the double helix, is both a marker of and a potential contributor to such pathology and has previously been reported to be elevated in the AD brain. In parallel, adenosine deaminase acting on RNA 1 (ADAR1) both binds and stabilises Z-DNA through its Zα domain and catalyses adenosine-to-inosine (A-to-I) editing of double-stranded RNA - an activity that suppresses inappropriate innate immune activation, and one whose loss, alongside elevated neuroinflammatory markers, is documented in AD. Together, these observations raise three questions: what does the Z-DNA structural shift mean for inflammation in AD; how does Z-DNA interact with ADAR1; and does this differ between the sexes?
Using Z-DNA immunoprecipitation and sequencing across post-mortem prefrontal cortex from AD and control donors, we found Z-DNA abundance to be greater in females than males, with this female bias amplified in disease. Subcellular fractionation and proteomics show ADAR1 to be globally downregulated in AD yet accumulated in the nucleus, consistent with a model that higher Z-DNA presence raises the probability of ADAR1 nuclear occupancy. Matched RNA-seq, using JACUSA2-based quantification of A-to-I editing at Alu elements, reveals significant alterations in editing rate in AD brain, indicating that ADAR1 functional output, not only its localisation, is disrupted. Together, these preliminary results suggest that increased Z-DNA in AD could sequester ADAR1 in the nucleus, thereby depleting the cytoplasmic pool available for A-to-I editing and promoting neuroinflammatory activity.
Ongoing work will utilise an oligonucleotide-based pulldown approach to capture Z-DNA-binding proteins together with functional manipulation of ADAR1 to establish the directionality and causality of the Z-DNA–ADAR1 interaction. Defining how ADAR1 activity is dysregulated offers a plausible mechanistic account of the sexual dimorphism of AD and, if borne out, nominates the ADAR1–Z-DNA axis as a novel therapeutic target.