Unraveling the neurological puzzle of long COVID: insights from extracellular vesicles

As the COVID-19 pandemic continues to unfold, scientists are unraveling a puzzling phenomenon known as Long COVID (LongC), where individuals experience persistent symptoms, including cognitive impairment, long after recovering from the acute phase of the illness. In a groundbreaking study, researchers at the University of California, San Francisco have explored the molecular details of LongC, shedding light on its neurological implications.

At the heart of this research are neuronal-enriched extracellular vesicles (nEVs), tiny particles released by cells that carry a cargo of proteins and other molecules. Previous studies have shown that nEVs from individuals with LongC contain proteins associated with Alzheimer’s disease (AD), suggesting a potential link between LongC and neurodegenerative disorders.

To further investigate this connection, the researchers developed a novel technique called EV Microfluidic Affinity Purification (EV-MAP) to isolate nEVs from plasma samples. By maximizing the yield of nEVs, scientists were able to analyze their protein content using advanced molecular profiling technology.

The results of this study are both intriguing and revealing. Among individuals with LongC and neurological complaints, the researchers identified a panel of proteins that were significantly increased compared to healthy controls. Interestingly, some of these proteins overlapped with those found in AD and HIV infection with mild cognitive impairment, suggesting common pathways underlying neurological dysfunction across these conditions.

Interactions of significant DE proteins of LongC, AD and HIV cohorts and significantly associated functional terms analyzed with String DB and Cytoscape.

One notable finding was the decreased expression of BST1, a protein implicated in immune regulation, in LongC and its increased expression in HIV infection. This suggests a complex interplay between immune dysregulation and neurological dysfunction in LongC.

Moreover, the identification of shared proteins between LongC and AD, such as MIF, ENO1, MESD, NUDT5, TNFSF14, and FYB1, provides valuable insights into the molecular mechanisms driving cognitive impairment in both conditions.

Overall, this study represents a crucial step forward in understanding the neurological effects of Long COVID. By unraveling the molecular signatures of LongC, these researchers are paving the way for targeted diagnostic and therapeutic interventions to alleviate the burden of this enigmatic condition.

Pulliam L, Sun B, McCafferty E, Soper SA, Witek MA, Hu M, Ford JM, Song S, Kapogiannis D, Glesby MJ, Merenstein D, Tien PC, Freasier H, French A, McKay H, Diaz MM, Ofotokun I, Lake JE, Margolick JB, Kim EY, Levine SR, Fischl MA, Li W, Martinson J, Tang N. (2024)  Microfluidic Isolation of Neuronal-Enriched Extracellular Vesicles Shows Distinct and Common Neurological Proteins in Long COVID, HIV Infection and Alzheimer’s Disease. Int J Mol Sci 5(7):3830. [article]

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