Journal
BRAIN
Volume 144, Issue -, Pages 3727-3741Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awab337
Keywords
OAS1; Alzheimer's disease; COVID-19; microglia; interferon
Categories
Funding
- Alzheimer Nederland
- Erasmus + Traineeship programme
- Eli Lilly and Co.
- Innovative Medicines Initiative 2 Joint Undertaking [115976]
- European Union's Horizon 2020 research and innovation programme
- European Federation of Pharmaceutical Industries and Associations (EFPIA)
- Leonard Wolfson Doctoral Training Fellowship in Neurodegeneration
- Science and Technology Agency, Seneca Foundation, CARM, Spain [00007/COVI/20]
- ARUK
- Dolby Foundation
- National Institute for Health Research University College London Hospitals Biomedical Research Centre
- Alzheimer's Research UK (ARUK) pump priming scheme via the UCL network
- UK DRI
- DRI Ltd - UK Medical Research Council
- Alzheimer's Society
- MRC [UKDRI-1009, UKDRI-1013] Funding Source: UKRI
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Recent research revealed a link between OAS1 gene and both Alzheimer's disease and severe outcomes of COVID-19, with decreased OAS1 expression potentially leading to increased inflammatory response. This finding may have implications for future treatments of Alzheimer's disease and COVID-19, as well as the development of disease progression biomarkers.
Recently, we reported oligoadenylate synthetase 1 (OAS1) contributed to the risk of Alzheimer's disease, by its enrichment in transcriptional networks expressed by microglia. However, the function of OAS1 within microglia was not known. Using genotyping from 1313 individuals with sporadic Alzheimer's disease and 1234 control individuals, we confirm the OAS1 variant, rs1131454, is associated with increased risk for Alzheimer's disease. The same OAS1 locus has been recently associated with severe coronavirus disease 2019 (COVID-19) outcomes, linking risk for both diseases. The single nucleotide polymorphisms rs1131454(A) and rs4766676(T) are associated with Alzheimer's disease, and rs10735079(A) and rs6489867(T) are associated with severe COVID-19, where the risk alleles are linked with decreased OAS1 expression. Analysing single-cell RNA-sequencing data of myeloid cells from Alzheimer's disease and COVID-19 patients, we identify co-expression networks containing interferon (IFN)-responsive genes, including OAS1, which are significantly upregulated with age and both diseases. In human induced pluripotent stem cell-derived microglia with lowered OAS1 expression, we show exaggerated production of TNF-alpha with IFN-gamma stimulation, indicating OAS1 is required to limit the pro-inflammatory response of myeloid cells. Collectively, our data support a link between genetic risk for Alzheimer's disease and susceptibility to critical illness with COVID-19 centred on OAS1, a finding with potential implications for future treatments of Alzheimer's disease and COVID-19, and development of biomarkers to track disease progression.
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