Microfluidic Isolation of Neuronal-Enriched Extracellular Vesicles Shows Distinct and Common Neurological Proteins in LC, HIV & AD, 2024, Pulliam+

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Microfluidic Isolation of Neuronal-Enriched Extracellular Vesicles Shows Distinct and Common Neurological Proteins in Long COVID, HIV Infection and Alzheimer’s Disease
Pulliam, Lynn; Sun, Bing; McCafferty, Erin; Soper, Steven A.; Witek, Malgorzata A.; Hu, Mengjia; Ford, Judith M.; Song, Sarah; Kapogiannis, Dimitrios; Glesby, Marshall J.; Merenstein, Daniel; Tien, Phyllis C.; Freasier, Heather; French, Audrey; McKay, Heather; Diaz, Monica M.; Ofotokun, Igho; Lake, Jordan E.; Margolick, Joseph B.; Kim, Eun-Young; Levine, Steven R.; Fischl, Margaret A.; Li, Wei; Martinson, Jeremy; Tang, Norina

Long COVID (LongC) is associated with a myriad of symptoms including cognitive impairment. We reported at the beginning of the COVID-19 pandemic that neuronal-enriched or L1CAM+ extracellular vesicles (nEVs) from people with LongC contained proteins associated with Alzheimer’s disease (AD). Since that time, a subset of people with prior COVID infection continue to report neurological problems more than three months after infection. Blood markers to better characterize LongC are elusive.

To further identify neuronal proteins associated with LongC, we maximized the number of nEVs isolated from plasma by developing a hybrid EV Microfluidic Affinity Purification (EV-MAP) technique. We isolated nEVs from people with LongC and neurological complaints, AD, and HIV infection with mild cognitive impairment.

Using the OLINK platform that assesses 384 neurological proteins, we identified 11 significant proteins increased in LongC and 2 decreased (BST1, GGT1). Fourteen proteins were increased in AD and forty proteins associated with HIV cognitive impairment were elevated with one decreased (IVD). One common protein (BST1) was decreased in LongC and increased in HIV. Six proteins (MIF, ENO1, MESD, NUDT5, TNFSF14 and FYB1) were expressed in both LongC and AD and no proteins were common to HIV and AD.

This study begins to identify differences and similarities in the neuronal response to LongC versus AD and HIV infection.

Link | PDF (International Journal of Molecular Sciences) [Open Access]

 

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Surprisingly, HIV, displaying BST1 was divergent the sole changes between these infections. from LongC and HIV, displaying divergent changes between these infections.

The one common protein between LongC and HIV was BST1 (bone marrow stromal cell antigen-1), also known as CD157. This protein is highly expressed in the embryonic brain where it regulates brain development. In the adult brain, BST-1 expression is more restricted, being expressed in neural stem cells surrounding glial cells, functioning to regulate adult neurogenesis, migration and integration of newly formed neurons into existing circuitry. BST1 is also expressed in dendritic cells and other cells of myelomonocytic lineage, thus playing a role in the innate immune response by controlling myeloid cell migration and diapedesis during inflammation. Interestingly, BST1 is decreased in LongC and increased in HIV nEVs.

Three of the best predictors for LongC proteins (MESD, TNFSF14 and BST1) have been linked to neuroinflammation and neurogenesis. MESD is a molecular chaperone for LRP5 and LRP6, and blocks Wnt/ β-catenin-mediated cell proliferation and migration. In the brain, blockage of Wnt signaling reduces neurogenesis in adult rat hippocampus. TNFSF14, also known as the LIGHT protein, has been shown to play a role in dendritic cell-mediated immune response by costimulating human T cell proliferation. Given these various reports, the findings in this study showing increased MESD, increased TNFSF14 and decreased BST1 may indicate the presence of neuroinflammation and diminished neurogenic capability in LongC individuals, which may affect the hippocampus region of the brain.

 

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GeneCards —

BST1
GGT1
MESD
TNFSF14