Microfluidic Isolation of Neuronal-Enriched Extracellular Vesicles Shows Distinct and Common Neurological Proteins in Long COVID, HIV Infection and Alzheimer’s Disease

Lynn Pulliam; Bing Sun; Erin McCafferty; Steven A. Soper; Malgorzata A. Witek; Mengjia Hu; Judith M. Ford; Sarah Song; Dimitrios Kapogiannis; Marshall J. Glesby; Daniel Merenstein; Phyllis C. Tien; Heather Freasier; Audrey French; Heather McKay; Monica M. Diaz; Igho Ofotokun; Jordan E. Lake; Joseph B. Margolick; Eun Young Kim; Steven R. Levine; Margaret A. Fischl; Wei Li; Jeremy Martinson; Norina Tang

doi:10.3390/ijms25073830

Microfluidic Isolation of Neuronal-Enriched Extracellular Vesicles Shows Distinct and Common Neurological Proteins in Long COVID, HIV Infection and Alzheimer’s Disease

Lynn Pulliam^*, Bing Sun, Erin McCafferty, Steven A. Soper, Malgorzata A. Witek, Mengjia Hu, Judith M. Ford, Sarah Song, Dimitrios Kapogiannis, Marshall J. Glesby, Daniel Merenstein, Phyllis C. Tien, Heather Freasier, Audrey French, Heather McKay, Monica M. Diaz, Igho Ofotokun, Jordan E. Lake, Joseph B. Margolick, Eun Young KimSteven R. Levine, Margaret A. Fischl, Wei Li, Jeremy Martinson, Norina Tang

^*Corresponding author for this work

Medicine, Infectious Diseases Division

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English (US)
Article number	3830
Journal	International journal of molecular sciences
Volume	25
Issue number	7
DOIs	https://doi.org/10.3390/ijms25073830
State	Published - Apr 2024

Funding

We thank Ivy Hsieh (San Francisco Veterans Administration Medical Center) for performing the transmission electron microscopy. This research was supported in part by the intramural research program of the National Institute on Aging, NIH. The authors gratefully acknowledge the contribution of the HIV study participants anad dedication of the staff at the MWCCS. The contents of this publication are solely the responsibility of the authors and do not represent the official views of the National Institutes of Health (NIH). MWCCS (Principal Investigators): Atlanta CRS (Ighovwerha Ofotokun, Anandi Sheth, and Gina Wingood), U01-HL146241; Baltimore CRS (Todd Brown and Joseph Margolick), U01-HL146201; Bronx CRS (Kathryn Anastos, David Hanna, and Anjali Sharma), U01-HL146204; Brooklyn CRS (Deborah Gustafson and Tracey Wilson), U01-HL146202; Data Analysis and Coordination Center (Gypsyamber D\u2019Souza, Stephen Gange and Elizabeth Topper), U01-HL146193; Chicago-Cook County CRS (Mardge Cohen and Audrey French), U01-HL146245; Chicago-Northwestern CRS (Steven Wolinsky, Frank Palella, and Valentina Stosor), U01-HL146240; Northern California CRS (Bradley Aouizerat, Jennifer Price, and Phyllis Tien), U01-HL146242; Los Angeles CRS (Roger Detels and Matthew Mimiaga), U01-HL146333; Metropolitan Washington CRS (Seble Kassaye and Daniel Merenstein), U01-HL146205; Miami CRS (Maria Alcaide, Margaret Fischl, and Deborah Jones), U01-HL146203; Pittsburgh CRS (Jeremy Martinson and Charles Rinaldo), U01-HL146208; UAB-MS CRS (Mirjam-Colette Kempf, Jodie Dionne-Odom, James B. Brock, and Deborah Konkle-Parker), U01-HL146192; UNC CRS (M. Bradley Drummond and Michelle Floris-Moore), U01-HL146194. The MWCCS is funded primarily by the National Heart, Lung, and Blood Institute (NHLBI), with additional co-funding from the Eunice Kennedy Shriver National Institute Of Child Health & Human Development (NICHD), National Institute On Aging (NIA), National Institute Of Dental & Craniofacial Research (NIDCR), National Institute Of Allergy And Infectious Diseases (NIAID), National Institute Of Neurological Disorders And Stroke (NINDS), National Institute Of Mental Health (NIMH), National Institute On Drug Abuse (NIDA), National Institute Of Nursing Research (NINR), National Cancer Institute (NCI), National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institute on Deafness and Other Communication Disorders (NIDCD), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute on Minority Health and Health Disparities (NIMHD), and in coordination and alignment with the research priorities of the National Institutes of Health, Office of AIDS Research (OAR). MWCCS data collection is also supported by UL1-TR000004 (UCSF CTSA), UL1-TR003098 (JHU ICTR), UL1-TR001881 (UCLA CTSI), P30-AI-050409 (Atlanta CFAR), P30-AI-073961 (Miami CFAR), P30-AI-050410 (UNC CFAR), P30-AI-027767 (UAB CFAR), P30-MH-116867 (Miami CHARM), UL1-TR001409 (DC CTSA), KL2-TR001432 (DC CTSA), and TL1-TR001431 (DC CTSA). This research was funded by the National Institute of Mental Health (L.P. R01 MH121121), Veterans Affairs Merit Award (J.M.F. and L.P. CX002322), Research Career Scientist Award (J.M.F. 1K6CX002519), the Biotechnology Resource Center of BioModular Multi-scale Systems for Precision Medicine (S.A.S. P41-EB020594) and the Kansas Institute for Precision Medicine (S.A.S. P20-GM130423).

Keywords

Alzheimer’s disease
HIV
L1CAM
OLINK
extracellular vesicles
long COVID
microfluidics

ASJC Scopus subject areas

Catalysis
Molecular Biology
Spectroscopy
Computer Science Applications
Physical and Theoretical Chemistry
Organic Chemistry
Inorganic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/ijms25073830

Cite this

Pulliam, L., Sun, B., McCafferty, E., Soper, S. A., Witek, M. A., Hu, M., Ford, J. M., Song, S., Kapogiannis, D., Glesby, M. J., Merenstein, D., Tien, P. C., Freasier, H., French, A., McKay, H., Diaz, M. M., Ofotokun, I., Lake, J. E., Margolick, J. B., ... 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. International journal of molecular sciences, 25(7), Article 3830. https://doi.org/10.3390/ijms25073830

@article{32ab949bd4bb489da5fb1350ae73dfd3,

title = "Microfluidic Isolation of Neuronal-Enriched Extracellular Vesicles Shows Distinct and Common Neurological Proteins in Long COVID, HIV Infection and Alzheimer{\textquoteright}s Disease",

abstract = "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{\textquoteright}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.",

keywords = "Alzheimer{\textquoteright}s disease, HIV, L1CAM, OLINK, extracellular vesicles, long COVID, microfluidics",

author = "Lynn Pulliam and Bing Sun and Erin McCafferty and Soper, {Steven A.} and Witek, {Malgorzata A.} and Mengjia Hu and Ford, {Judith M.} and Sarah Song and Dimitrios Kapogiannis and Glesby, {Marshall J.} and Daniel Merenstein and Tien, {Phyllis C.} and Heather Freasier and Audrey French and Heather McKay and Diaz, {Monica M.} and Igho Ofotokun and Lake, {Jordan E.} and Margolick, {Joseph B.} and Kim, {Eun Young} and Levine, {Steven R.} and Fischl, {Margaret A.} and Wei Li and Jeremy Martinson and Norina Tang",

note = "Publisher Copyright: {\textcopyright} 2024 by the authors.",

year = "2024",

month = apr,

doi = "10.3390/ijms25073830",

language = "English (US)",

volume = "25",

journal = "International journal of molecular sciences",

issn = "1661-6596",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "7",

}

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', International journal of molecular sciences, vol. 25, no. 7, 3830. https://doi.org/10.3390/ijms25073830

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 et al.
In: International journal of molecular sciences, Vol. 25, No. 7, 3830, 04.2024.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Microfluidic Isolation of Neuronal-Enriched Extracellular Vesicles Shows Distinct and Common Neurological Proteins in Long COVID, HIV Infection and Alzheimer’s Disease

AU - Pulliam, Lynn

AU - Sun, Bing

AU - McCafferty, Erin

AU - Soper, Steven A.

AU - Witek, Malgorzata A.

AU - Hu, Mengjia

AU - Ford, Judith M.

AU - Song, Sarah

AU - Kapogiannis, Dimitrios

AU - Glesby, Marshall J.

AU - Merenstein, Daniel

AU - Tien, Phyllis C.

AU - Freasier, Heather

AU - French, Audrey

AU - McKay, Heather

AU - Diaz, Monica M.

AU - Ofotokun, Igho

AU - Lake, Jordan E.

AU - Margolick, Joseph B.

AU - Kim, Eun Young

AU - Levine, Steven R.

AU - Fischl, Margaret A.

AU - Li, Wei

AU - Martinson, Jeremy

AU - Tang, Norina

PY - 2024/4

Y1 - 2024/4

N2 - 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.

AB - 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.

KW - Alzheimer’s disease

KW - HIV

KW - L1CAM

KW - OLINK

KW - extracellular vesicles

KW - long COVID

KW - microfluidics

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UR - http://www.scopus.com/inward/citedby.url?scp=85190359612&partnerID=8YFLogxK

U2 - 10.3390/ijms25073830

DO - 10.3390/ijms25073830

M3 - Article

C2 - 38612641

AN - SCOPUS:85190359612

SN - 1661-6596

VL - 25

JO - International journal of molecular sciences

JF - International journal of molecular sciences

IS - 7

M1 - 3830

ER -

Microfluidic Isolation of Neuronal-Enriched Extracellular Vesicles Shows Distinct and Common Neurological Proteins in Long COVID, HIV Infection and Alzheimer’s Disease

Abstract

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Keywords

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UN SDGs

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