@article{ff5e4cb7ebf2432ba8860fbb205ef9ac,
title = "Brain Tissue-Derived Extracellular Vesicles in Alzheimer's Disease Display Altered Key Protein Levels Including Cell Type-Specific Markers",
abstract = "BACKGROUND: Brain tissue-derived extracellular vesicles (bdEVs) play neurodegenerative and protective roles, including in Alzheimer's disease (AD). Extracellular vesicles (EVs) may also leave the brain to betray the state of the CNS in the periphery. Only a few studies have profiled the proteome of bdEVs and source brain tissue. Additionally, studies focusing on bdEV cell type-specific surface markers are rare. OBJECTIVE: We aimed to reveal the pathological mechanisms inside the brain by profiling the tissue and bdEV proteomes in AD patients. In addition, to indicate targets for capturing and molecular profiling of bdEVs in the periphery, CNS cell-specific markers were profiled on the intact bdEV surface. METHODS: bdEVs were separated and followed by EV counting and sizing. Brain tissue and bdEVs from age-matched AD patients and controls were then proteomically profiled. Total tau (t-tau), phosphorylated tau (p-tau), and antioxidant peroxiredoxins (PRDX) 1 and 6 were measured by immunoassay in an independent bdEV separation. Neuron, microglia, astrocyte, and endothelia markers were detected on intact EVs by multiplexed ELISA. RESULTS: Overall, concentration of recovered bdEVs was not affected by AD. Proteome differences between AD and control were more pronounced for bdEVs than for brain tissue. Levels of t-tau, p-tau, PRDX1, and PRDX6 were significantly elevated in AD bdEVs compared with controls. Release of certain cell-specific bdEV markers was increased in AD. CONCLUSION: Several bdEV proteins are involved in AD mechanisms and may be used for disease monitoring. The identified CNS cell markers may be useful tools for peripheral bdEV capture.",
keywords = "Alzheimer's disease, brain, cell of origin markers, central nervous system, ectosomes, exosomes, extracellular vesicles, microvesicles, proteomics",
author = "Yiyao Huang and Driedonks, {Tom A.P.} and Lesley Cheng and Harinda Rajapaksha and Routenberg, {David A.} and Rajini Nagaraj and Javier Redding and Tanina Arab and Powell, {Bonita H.} and Olga Pletnikov{\'a} and Troncoso, {Juan C.} and Lei Zheng and Hill, {Andrew F.} and Vasiliki Mahairaki and Witwer, {Kenneth W.}",
note = "Funding Information: VM and KWW gratefully acknowledge support from the Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease including helpful comments and advice from founder and director Constantine Lyketsos. Thanks to: Kenneth Pienta, Johns Hopkins University School of Medicine, for access to the Nanoflow FCM (NFCM) platform; Mitchell Science Writing for manuscript editing and citation formatting; and the La Trobe University Comprehensive Proteomics Platform. We also thank members of the Witwer and Retrovirus Laboratories, Johns Hopkins University School of Medicine, and various members of the International Society for Extracellular Vesicles for valuable discussions and support. This work was supported in part by grants from the US National Institutes of Health: AI144997 (to KWW, with support for TAPD), MH118164 and AG057430 (to VM and KWW), UG3 and UH3 CA241694 (to KWW), UH2MH118167 (to DAR), supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director, and by the National Health and Medical Research Council of Australia (GNT1132604 to AFH). JHU Alzheimer's Disease Research Centers NIH P30 AG 066507 and BIOCARD NIH U19AG033655. Authors' disclosures available online (https:// www.j-alz.com/manuscript-disclosures/22-0322r2). Funding Information: VM and KWW gratefully acknowledge support from the Richman Family Precision Medicine Center of Excellence in Alzheimer{\textquoteright}s Disease including helpful comments and advice from founder and director Constantine Lyketsos. Thanks to: Kenneth Pienta, Johns Hopkins University School of Medicine, for access to the Nanoflow FCM (NFCM) platform; Mitchell Science Writing for manuscript editing and citation formatting; and the La Trobe University Comprehensive Proteomics Platform. We also thank members of the Witwer and Retrovirus Laboratories, Johns Hopkins University School of Medicine, and various members of the International Society for Extracellular Vesicles for valuable discussions and support. Publisher Copyright: {\textcopyright} 2022 - The authors. Published by IOS Press.",
year = "2022",
doi = "10.3233/JAD-220322",
language = "English",
volume = "90",
pages = "1057--1072",
journal = "Journal of Alzheimer's Disease",
issn = "1387-2877",
publisher = "IOS Press",
number = "3",
}