TY - JOUR
T1 - Human neural cell type-specific extracellular vesicle proteome defines disease-related molecules associated with activated astrocytes in Alzheimer's disease brain
AU - You, Yang
AU - Muraoka, Satoshi
AU - Jedrychowski, Mark P.
AU - Hu, Jianqiao
AU - McQuade, Amanda K.
AU - Young-Pearse, Tracy
AU - Aslebagh, Roshanak
AU - Shaffer, Scott A.
AU - Gygi, Steven P.
AU - Blurton-Jones, Mathew
AU - Poon, Wayne W.
AU - Ikezu, Tsuneya
N1 - Funding Information:
We would like to thank the staff members of the Laboratory of Molecular NeuroTherapeutics at Boston University and Mayo Clinic Florida for technical assistance, NIH NeuroBioBank for unfixed human frozen brain tissues, and M. Ericsson (Electron Microscopy Facility, Harvard Medical School) for electron microscope imaging services. We also thank BioRender.com for providing resources and templates for the illustrations. This work was funded in part by AbbVie, Inc. (TI), Alzheimer's Association AARF‐9550302678 (SM), Alzheimer's Research UK (TI), Cure Alzheimer's Fund (TI), NIH RF1 AG054199 (TI), NIH R01 AG054672 (TI), NIH R01 AG066429 (TI), NIH R01 AG072719 (TI), NIH R01 AG067763 (TI), and NIH R21 NS104609 (TI).
Funding Information:
We would like to thank the staff members of the Laboratory of Molecular NeuroTherapeutics at Boston University and Mayo Clinic Florida for technical assistance, NIH NeuroBioBank for unfixed human frozen brain tissues, and M. Ericsson (Electron Microscopy Facility, Harvard Medical School) for electron microscope imaging services. We also thank BioRender.com for providing resources and templates for the illustrations. This work was funded in part by AbbVie, Inc. (TI), Alzheimer's Association AARF-9550302678 (SM), Alzheimer's Research UK (TI), Cure Alzheimer's Fund (TI), NIH RF1 AG054199 (TI), NIH R01 AG054672 (TI), NIH R01 AG066429 (TI), NIH R01 AG072719 (TI), NIH R01 AG067763 (TI), and NIH R21 NS104609 (TI).
Publisher Copyright:
© 2021 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles
PY - 2022/1
Y1 - 2022/1
N2 - In neurodegenerative diseases, extracellular vesicles (EVs) transfer pathogenic molecules and are consequently involved in disease progression. We have investigated the proteomic profiles of EVs that were isolated from four different human-induced pluripotent stem cell-derived neural cell types (excitatory neurons, astrocytes, microglia-like cells, and oligodendrocyte-like cells). Novel cell type-specific EV protein markers were then identified for the excitatory neurons (ATP1A3, NCAM1), astrocytes (LRP1, ITGA6), microglia-like cells (ITGAM, LCP1), and oligodendrocyte-like cells (LAMP2, FTH1), as well as 16 pan-EV marker candidates, including integrins and annexins. To further demonstrate how cell-type-specific EVs may be involved in Alzheimer's disease (AD), we performed protein co-expression network analysis and conducted cell type assessments for the proteomes of brain-derived EVs from the control, mild cognitive impairment, and AD cases. A protein module enriched in astrocyte-specific EV markers was most significantly associated with the AD pathology and cognitive impairment, suggesting an important role in AD progression. The hub protein from this module, integrin-β1 (ITGB1), was found to be significantly elevated in astrocyte-specific EVs enriched from the total brain-derived AD EVs and associated with the brain β-amyloid and tau load in independent cohorts. Thus, our study provides a featured framework and rich resource for the future analyses of EV functions in neurodegenerative diseases in a cell type-specific manner.
AB - In neurodegenerative diseases, extracellular vesicles (EVs) transfer pathogenic molecules and are consequently involved in disease progression. We have investigated the proteomic profiles of EVs that were isolated from four different human-induced pluripotent stem cell-derived neural cell types (excitatory neurons, astrocytes, microglia-like cells, and oligodendrocyte-like cells). Novel cell type-specific EV protein markers were then identified for the excitatory neurons (ATP1A3, NCAM1), astrocytes (LRP1, ITGA6), microglia-like cells (ITGAM, LCP1), and oligodendrocyte-like cells (LAMP2, FTH1), as well as 16 pan-EV marker candidates, including integrins and annexins. To further demonstrate how cell-type-specific EVs may be involved in Alzheimer's disease (AD), we performed protein co-expression network analysis and conducted cell type assessments for the proteomes of brain-derived EVs from the control, mild cognitive impairment, and AD cases. A protein module enriched in astrocyte-specific EV markers was most significantly associated with the AD pathology and cognitive impairment, suggesting an important role in AD progression. The hub protein from this module, integrin-β1 (ITGB1), was found to be significantly elevated in astrocyte-specific EVs enriched from the total brain-derived AD EVs and associated with the brain β-amyloid and tau load in independent cohorts. Thus, our study provides a featured framework and rich resource for the future analyses of EV functions in neurodegenerative diseases in a cell type-specific manner.
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U2 - 10.1002/jev2.12183
DO - 10.1002/jev2.12183
M3 - Article
C2 - 35029059
AN - SCOPUS:85123468510
VL - 11
JO - Journal of Extracellular Vesicles
JF - Journal of Extracellular Vesicles
SN - 2001-3078
IS - 1
M1 - e12183
ER -