Lee et al. (2025)
- Authors: Hye-Kyung Lee, Ji Young Choi, Jung Hyun Park, Moon Han Chang, Jung Ho Park, Young Ho Koh
- Institutes: Division of Brain Diseases Research, Department of Chronic Disease Convergence Research, Korea National Institute of Health, Cheongju-si, Republic of Korea, Nexmos Inc., Yongin-si, Gyeonggi-do, Republic of Korea
- Publisher: PLOS ONE
- Link: DOI
Summary
This study maps a direct molecular pathway between the SARS-CoV-2 spike protein and the development of ‘brain fog’ and neurodegenerative markers. It demonstrates that the viral protein can trick brain cells into a state of hypoxia-like dysfunction, leading to the clumping of toxic proteins similar to those found in Alzheimer’s and Parkinson’s diseases. Crucially, the research identifies metformin 💊 as a potential treatment that can block this damage and restore healthy brain gene expression. These findings provide a scientific foundation for clinical trials using this existing, low-cost medication to help patients suffering from Long COVID cognitive decline.
What was researched?
The study investigated the molecular mechanisms through which the SARS-CoV-2 S1 spike protein causes cognitive impairment and memory loss. It specifically explored whether the common diabetes medication metformin 💊 could prevent or reverse these neurological changes.
Why was it researched?
While many COVID-19 survivors experience persistent ‘brain fog,’ the exact process of how the virus affects the brain’s internal hardware remained unclear. Researchers wanted to understand if the persistent presence of viral proteins contributes to long-term cognitive decline and neurodegeneration.
How was it researched?
The researchers used a rat model where the S1 spike protein was administered intranasally to see how it affected brain tissue and behavior over six weeks. They also conducted genetic analysis (mRNA sequencing) and used human neuronal cell lines to study how the protein interacts with cellular switches like HIF-1α.
What has been found?
The spike protein entered the brain and stabilized a protein called HIF-1α, which acted as a faulty switch that turned off genes required for healthy brain connections (synapses). By six weeks, this process led to significant neuronal loss and the accumulation of toxic proteins, including phosphorylated tau and alpha-synuclein. Metformin was found to block this ‘hypoxia’ switch and significantly reduce the clumping of these harmful proteins, effectively protecting the brain’s cognitive function.
Discussion
The study suggests that cognitive damage from COVID-19 is not just general inflammation but a specific genetic disruption that mirrors early neurodegenerative disease. While the results are promising, the researchers note that the spike protein behavior in a chronic infection model may differ from the temporary exposure seen in vaccinations.
Conclusion & Future Work
The SARS-CoV-2 spike protein directly triggers a cascade leading to memory loss and neurodegenerative-like protein clumping. Metformin is a viable candidate for therapeutic intervention to mitigate the long-term cognitive consequences of COVID-19.