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At the onset of the COVID-19 pandemic, people with Alzheimer’s disease were identified as having an increased risk of developing severe COVID-19. “At first, we thought it was because people with dementia were less likely to be able to respect physical distancing and mask wear, or were exposed in their care facilities when there was a mass discharge of drugs. hospitals, “Dr David Strain, senior clinician professor at the University of Exeter said. “However, even after adjusting for these risk factors, people with even early-onset dementia were still at a much higher risk.”
A new study by Dr Dervis Salih and colleagues at University College London (UCL) suggests that an antiviral gene, OAS1, could contribute to this observed association. The results are published in the journal Brain.
OAS1 and Alzheimer’s disease
The new study builds on previous work by the UCL team that reported a link between oligoadenylate synthetase 1 (OAS1) and Alzheimer’s disease. The OAS1 The gene is expressed in microglia, an immune cell which makes up about 10-15% of cells in the brain. While the hallmark of Alzheimer’s disease pathology is a buildup of amyloid plaques and TAU tangles in the brain, a growing body of research shows how the immune system – and especially inflammation – contributes to it.
What is the function of OAS1?
There are three forms of OAS proteins expressed in the human body: OAS1, OAS2 and OAS3. Each form is induced by the action of interferons, a group of cytokine proteins that activate a myriad of defense mechanisms in the immune system. Upon activation, OAS1 and OAS2 trigger the production of oligoadenylates and activate an enzyme known as RNase L, which digests RNA.
Variants and increased risk of disease
Genetic variants exist between individuals and can lead to the production of a variant form of a protein. Under certain circumstances, the protein variant may be defective or even absent; disrupt the typical function that is performed in a cell or molecular pathway.
In a genome-wide association study (GWAS) involving 2,547 people – 50% of whom had Alzheimer’s disease – Salih and his colleagues identified a variant of the OAS1 gene, known as rs1131454, which was linked to an increased likelihood of having the disease.
The researchers also found that four variants of the OAS1 gene associated with increased susceptibility to Alzheimer’s disease had recently been highlighted in COVID-19 research. The data suggested that having such variants resulted in an increased baseline risk of requiring intensive care treatment.
At the molecular level, UCL researchers found that all four variants are associated with decreased expression of the OAS1 protein. Using models of COVID-19 immune cells, they found that when microglia were treated to have reduced expression of the OAS1 gene, a “cytokine storm” has been unleashed. Hyper-inflammation and cytokine storm syndrome (CSS) have been identified in many patients for whom COVID-19 has been shown to be fatal.
How to apply this research?
Correlation does not prove causation, and this is a limitation associated with GWAS studies. It is not because a certain variant is associated with a disease that it confirms that it cause disease.
That being said, there is some useful information to be gleaned from the new study, Strain said: “We know that one of the key pathways in the development of Alzheimer’s disease is inflammation in brain tissue, and, As our understanding of the pandemic has grown, we have seen many other inflammatory conditions highlighted as risk factors for poor outcomes, so the results are not too surprising. This adds important information as to the pathogenesis of the presentations more severe COVID and hopefully may shed more light on potential treatment options or even personalized preventive medicine.
The development of a method to analyze genetic variants in individuals who test positive for COVID-19 could be used to identify those at risk of requiring intensive care, Salih said. “There is still a lot of work to be done to get us there. Likewise, we hope that our research could fuel the development of a blood test to identify if someone is at risk of developing Alzheimer’s disease before showing any signs. memory problems, ”he added.
Reference: Magusali N, Graham AC, Piers TM, et al. A genetic link between the risk of Alzheimer’s disease and the serious consequences of COVID-19 via the OAS1 uncomfortable. Brain. 2021; (awab337). doi: 10.1093 / brain / awab337
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