OAS1: A Protective Mechanism for Alzheimer's Disease? An Exploration of Data and Possible Mechanisms.

The immune system and neuroinflammation are now well established in the aetiology of neurodegeneration. Previous studies of transcriptomic and gene association studies have highlighted the potential of the 2'-5' oligoadenylate synthetase 1 (OAS1) to play a role in Alzheimer's disease. OAS1 is a viral response gene, interferon-induced, dsRNA activated enzyme, which binds RNase L to degrade dsRNA, and has been associated with COVID-19 response. This study explores whether a viral defence gene could play a vital role in neurodegeneration pathology. The genotyping of five SNPs across the locus was conducted in the Brains for Dementia Research (BDR) Cohort for association with AD. RNA-sequencing data were explored for differences in gene expression between phenotypes and genotypes. Finally, levels of dsRNA were measured in control cell lines, prior to and after exposure to amyloid oligomers and in cells harbouring a dementia-relevant mutation. No association of any of the SNPs investigated were associated with the AD phenotype in the BDR cohort. However, gene expression data supported the previous observation that the minor allele haplotype was associated with higher levels of the gene expression and the presence of an alternative transcript. Further to this, the presence of endogenous dsRNA was found to increase with exposure to amyloid oligomers and in the cell line with a dementia-relevant mutation. The data presented here suggest further exploration of the gene in relation to dementia is warranted. Investigations of whether carriers of the protective haplotype lower dsRNA presence and in turn lower inflammation and cell death are required to support the role of the gene as a moderator of neurodegeneration.