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

Badhwar, A.; Hirschberg, Y.; Tamayo, N. V.; Iulita, M. F.; Udeh-Momoh, C. T.; Matton, A.; Tarawneh, R. M.; Rissman, R. A.; Ledreux, A.; Winston, C. N.; Haqqani, A. S.; Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment, BBB-EWG,

doi:10.1101/2023.10.02.560210

bioRxiv · 10.1101/2023.10.02.560210

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

Badhwar, A.·Hirschberg, Y.·Tamayo, N. V.·Iulita, M. F.·Udeh-Momoh, C. T.·Matton, A.·Tarawneh, R. M.·Rissman, R. A.·Ledreux, A.·Winston, C. N.·Haqqani, A. S.·Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment, BBB-EWG,

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Abstract

INTRODUCTIONBrain-derived extracellular vesicles (BEVs) in blood allows for minimally- invasive investigations of 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. METHODSNDD 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. RESULTS82.1% of studies used polymer-based (ExoQuick) EV-enrichment, and 92.3% used L1CAM for IP-based BEV-enrichment. Centrifugation times differed across studies. 26.8% of 82 proteins systematically identified were CNS-specific: 50% ECD+, 77.3% were listed in EV- databases. DISCUSSIONWe identified protocol steps requiring standardization, and recommend additional CNS-specific proteins that can be used for BEV-enrichment or as BEV-biomarkers.

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Badhwar, A., Hirschberg, Y., Tamayo, N. V., Iulita, M. F., Udeh-Momoh, C. T., Matton, A., Tarawneh, R. M., Rissman, R. A., Ledreux, A., Winston, C. N., Haqqani, A. S., Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment, BBB-EWG,. 2023-10-02. Assessment of brain-derived extracellular vesicle enrichment for blood biomarker analysis in age-related neurodegenerative diseases: An international overview. https://doi.org/10.1101/2023.10.02.560210

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