Human neural cell type-specific extracellular vesicle proteome defines disease-related molecules associated with activated astrocytes in Alzheimer's disease brain

J Extracell Vesicles. 2022 Jan;11(1):e12183. doi: 10.1002/jev2.12183.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism
  • Astrocytes / metabolism*
  • Biomarkers / metabolism
  • Brain / cytology
  • Brain / metabolism*
  • Cognitive Dysfunction / metabolism
  • Cognitive Dysfunction / pathology
  • Extracellular Vesicles / metabolism*
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Integrin beta1 / metabolism
  • Proteome / metabolism
  • tau Proteins / metabolism


  • Amyloid beta-Peptides
  • Biomarkers
  • Integrin beta1
  • Itgb1 protein, human
  • Proteome
  • tau Proteins