Assessment of brain‐derived extracellular vesicle enrichment for blood biomarker analysis in age‐related neurodegenerative diseases: An international overview

• Published in: Alzheimer's & dementia Vol. 20; no. 7; pp. 4411 - 4422
• Main Authors: Badhwar, AmanPreet, Hirschberg, Yael, Valle‐Tamayo, Natalia, Iulita, M. Florencia, Udeh‐Momoh, Chinedu T., Matton, Anna, Tarawneh, Rawan M., Rissman, Robert A., Ledreux, Aurélie, Winston, Charisse N., Haqqani, Arsalan S.
• Format: Journal Article
• Language: English
• Published: United States John Wiley and Sons Inc 01-07-2024
• Subjects: age‐related neurodegenerative diseases; Alzheimer's disease; biofluid based biomarkers; blood; brain‐derived extracellular vesicles; exosomes; immunoprecipitation‐based enrichment; Medicin och hälsovetenskap; microvesicles; novel biomarkers; protocol variability; age‐related neurodegenerative diseases; exosomes; brain‐derived extracellular vesicles; novel biomarkers; protocol variability; microvesicles; Alzheimer's disease; blood; immunoprecipitation‐based enrichment; biofluid based biomarkers
• ISSN: 1552-5260; 1552-5279; 1552-5279
• DOI: 10.1002/alz.13823

INTRODUCTION
Brain‐derived extracellular vesicles (BEVs) in blood allows for minimally‐invasive investigations of central nervous system (CNS) ‐specific markers of age‐related neurodegenerative diseases (NDDs). Polymer‐based EV‐ and immunoprecipitation (IP)‐based BEV‐enrichment protocols from blood have gained popularity. We systematically investigated protocol consistency across studies, and determined CNS‐specificity of proteins associated with these protocols.
METHODS
NDD articles investigating BEVs in blood using polymer‐based and/or IP‐based BEV enrichment protocols were systematically identified, and protocols compared. Proteins used for BEV‐enrichment and/or post‐enrichment were assessed for CNS‐ and brain‐cell‐type‐specificity, extracellular domains (ECD+), and presence in EV‐databases.
RESULTS
A total of 82.1% of studies used polymer‐based (ExoQuick) EV‐enrichment, and 92.3% used L1CAM for IP‐based BEV‐enrichment. Centrifugation times differed across studies. A total of 26.8% of 82 proteins systematically identified were CNS‐specific: 50% ECD+, 77.3% were listed in EV‐databases.
CONCLUSIONS
We identified protocol steps requiring standardization, and recommend additional CNS‐specific proteins that can be used for BEV‐enrichment or as BEV‐biomarkers.
Highlights
Across NDDs, we identified protocols commonly used for EV/BEV enrichment from blood.
We identified protocol steps showing variability that require harmonization.
We assessed CNS‐specificity of proteins used for BEV‐enrichment or found in BEV cargo.
CNS‐specific EV proteins with ECD+ or without were identified.
We recommend evaluation of blood‐BEV enrichment using these additional ECD+ proteins.