Previous research has identified the interferon-responsive OAS1 gene as a risk gene for Alzheimer’s disease. OAS1 is an enzyme that binds to two strands of RNA and stimulates the conjunctiva to form oligoadenylates. They also activate RNase L to break down RNA.
Researchers led by Dervis A. Salih of UCL’s UK Dementia Research Institute have recently expanded on these findings. They found that a decrease in OASI gene expression was associated with the development of Alzheimer’s disease. Low sensitivity from OAS1 variants also stimulated an inflammatory response, which may contribute to severe symptoms in COVID-19 disease.
The authors write:
“Our data show that OAS1 is required to limit the pro-inflammatory response of myeloid cells when stimulated by IFN-γ. We also identify SNPs within AD-associated OAS1 in the only locus leading to acute illness with COVID-19… Further study of OAS1 activity in tissue immune cells and the genetic network involved in OAS1 will provide better molecular targets for monitoring disease progression and treatment of AD, as well as COVID-19 and possibly its long-acting sequelae. “
The findings could help with future therapeutic treatment for Alzheimer’s and COVID-19 by treating OASI changes. The risk gene may also be beneficial in predicting the onset of the disease.
The study “Genetic variability associated with OAS1 expression in myeloid cells increases the risk of Alzheimer’s disease and adverse effects of COVID-19” is available as a preview of the bioRxiv* server, while the article is under peer review.
Rs1131454 within OAS1 is associated with Alzheimer’s and severe COVID-19 infection
The research team generated 1,313 participants with sporadic Alzheimer’s disease and 1,234 participants who were controls. Genotyping results identified rs1131454 in the OAS1 gene are linked to Alzheimer’s disease. The presence of rs1131454 was associated with severe COVID-19 disease, indicating that the gene variant affects both Alzheimer’s disease and SARS-CoV-2 disease.
The team then used scRNA-seq of isolated mouse microglia to construct genetic transcription networks. They found an interferon response pathway with increased expression of Oas1a as they mature in microglia. The results indicate that the interferon pathway occurs in the undergrowth of tissue immune cells. Thus changes in genetic expression from aging may improve or reduce the risk of age-related diseases.
Differentiation of OAS1 affects inflammatory response
Autopsies of individuals who died from Alzheimer’s showed interferon-responsive genes with OAS1 in human microglia. Using genes similar to human microglia, they showed that the OAS1 gene was the culture behind the pro-inflammatory response received by myeloid cells when exposed to increased interferon levels.
Reduced OAS1 levels were more likely to elicit a strong pro-inflammatory response and were associated with Alzheimer’s and COVID-19. The researchers suggest that the eQTL variables contributed to lower OAS1 levels. People with eQTL mutations on the OAS1 gene are more likely to damage the neurons and alveolar cells by triggering a cytokine storm.
Using siRNA, the team reduced OAS1 expression to mimic the eQTL difference. They found that the gene plays a crucial role in attenuating the pro-inflammatory signal TNF-α when IFN-γ levels rise.
A gene model associated with interferon response is present on the pathway of a specific microglial action pathway regulated in aged mice, mice with amyloid pathology and in humans with AD. A) The genetic network in which Oas1a from microglial cells is isolated from wild-type mice and APPNL-GF KI at 3, 6, 12, and 21 months of age was screened by scRNA-seq (Sala Frigerio et al., 2019) . The 50 genes showing the highest affinity are plotted, and Oas1a is identified. Green nodes represent genes, peripheral lines represent connective nodes, and the large red nodes in the middle are hub genes (full network given in Table S2). (B) Semi-directed pseudotime sequence of microglial cells separated from wild-type mice and APPNL-GF KI as above based on sensitivity (Sala Frigerio et al., 2019), by Monocle 2, showing homeostatic cells as the basic state, and ARM and IRM as specific action endpoints. C) The gene model containing Oas1a is circulating throughout the IRM-associated activation pathway. The expression of this model is virtually absent from both the root homeostatic state and the ARM pathway. D) The normal expression of the 60 largest genes in the median interferon response is greater in isolated microglia from wild-type age compared with young adult mice (6–8-weeks versus 16–18-months-old ; N = 6 mice per group.Data are shown as mean ± SEM.Student test; ** p <0.01.Further analysis of data from O'Neil et al. (2018)). E) The normal expression of the 60 largest genes in the median interferon response is greater in isolated microglia from PSEN2 / APP compared with wild-type mice at 14–15-months of age (N = 6–9 mice per group. shown as mean ± SEM.Student t-test; **** p <0.0001. Further analysis of data from Friedman et al. (2018)). F) Genetic network plot of model related to interferon response detected in microglial cells isolated from human AD patients and individuals with MCI (Olah et al., 2020). This model shows a large overlap with the interferon response model detected in mice (see panel A) (full network given in Table S3). The main gene of this model is CD163, and several other macrophage signal genes are evident within this model (MSR1, TGFB1, F13A1, LY6E and LYZ), expressing that expression of OAS1 and interferon response genes other in human AD patients the brain is either associated with a population of borderline-bound or invading CNS macrophages, or may be involved in microglial subpopulation that progresses against anti-inflammatory genes. OAS1 is highlighted.
Increased inflammation inhibits TREM2 expression
The team also maintained that high levels of IFN-γ and TNF-α inhibited TREM2 expression.
“Because TREM2 appears to have a protective role in AD and slow disease progression, elevated pro-inflammatory symptoms may increase AD risk and progression by suppressing this protective signal. TNF-α is also present. activates PKR / EIF2αK2, which is downstream of interferon signaling through TLR4, resulting in the protein activator of the IFN-inducible protein kinase (PRKRA) leading to apoptosis, ”the researchers wrote.
Their findings indicate that high levels of IFN symptoms combined with TNF-α release may be the mechanism behind dementia.
Although, an increase in interferon-responsive genes – Oas1a and family members Mx1, Stat1 / 2, Ifit3, Ifitm3, and Usp18 – with age may limit the extent of damage caused by associated pro-inflammatory symptoms ri aois. Considering old age a high-risk factor for COVID-19 disease and mortality, the researchers suggest that understanding changes with OAS1a expression may help reduce the cell damage associated with age that contributes to the development of diseases.
* Important message
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