Can SARS-CoV-2 proteins accelerate Abeta pathology in fly and mouse models of AD?

The onset of the COVID-19 epidemic in December 2019, caused by the novel SARS-CoV-2 coronavirus, unleashed a catastrophic toll, claiming over 7 million lives and imposing an unparalleled strain over the healthcare, social, and financial systems worldwide. Although COVID-19 is no longer a global emergency, the healthcare burden continues. This is because thousands of people have experienced multiple neurological symptoms for months or even years after the initial infection, which is referred to as Long Covid. These symptoms include "brain fog", persistent headache, disturbed consciousness, fatigue, and cognitive decline to name a few. Unfortunately, hardly anything is known about the molecular underpinnings of these prolonged neurological manifestations and the potential involvement of SARS-Co-V2 proteins in the onset of degenerative dementias like Alzheimer's disease (AD). To address this gap, we screened all 29 proteins encoded by the SARS-CoV-2 genome and found one non-structural protein that induces a very aggressive phenotype when expressed in the eye of transgenic flies as well as loss of axonal projections when expressed in the Drosophila brain mushroom body neurons, which are associated with memory functions. Strikingly, we also found that this protein aggravates Abeta42-dependent neurodegeneration and dramatically exacerbates Abeta42 aggregation as evidenced by thioflavin staining. This suggests that the potential presence of this SARS-CoV-2 protein in the brain could trigger a response to influence the development of Alzheimer's disease. To test this hypothesis, we will perform an age-dependent study of the neurotoxic role of this protein in a Drosophila model of Abeta42 deposition using genetic, molecular and behavioral approaches (Aim1) as well as a comprehensive pathological analysis in mouse models of Alzheimer's disease (Aim2). This complementary work in flies and mice is highly significant because it may uncover a groundbreaking pathological association between coronavirus proteins and Alzheimer's disease. In addition, it may also lead to a paradigm shift to guide new research priorities to prevent a potentially devastating public health crisis in the future.