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PXD028898-1

PXD028898 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleMulti-omics analysis of microglial extracellular vesicles from human Alzheimer’s Disease brain reveals disease-associated signatures
DescriptionAlzheimer’s Disease (AD) is the most common cause of dementia in the elderly population without a cure or early diagnostics currently available. Despite the demonstrated ability of extracellular vesicles (EVs) to spread tau and Aβ pathology in AD models and their potential utility as a diagnostic and treatment-monitoring tool, our knowledge of human brain EV subpopulations, their molecular composition and roles in disease progression is very limited. Genome-wide association studies linked multiple AD genetic risk factors to microglia-specific pathways suggesting a potential role of microglia-derived EVs in AD progression. Here we are presenting a method for isolation of microglial CD11b-positive small EVs from cryopreserved human brain tissue and multi-omics analysis of the EVs from the parietal cortex of 4 late-stage AD (Braak V-VI) and 3 age-matched normal/low pathology (NL) cases. We identified a total of 1000 proteins by quantitative proteomics, analyzed 594 individual lipid species by targeted lipidomics, and 105 miRNAs using a NanoString miRNA expression panel. We found significant reduction in abundance of homeostatic microglia markers, P2RY12 and TMEM119, and increased levels of disease associated microglia markers, FTH1 and TREM2, in microglial EVs from AD brain compared to NL cases. Protein tau abundance was also significantly higher in AD brain-derived microglial EVs. These changes were accompanied by upregulation of synaptic and neuron-specific proteins in the AD group. Levels of free-cholesterol were elevated in microglial EVs from AD brain. Lipidomic analysis also revealed a pro-inflammatory lipid profile, endolysosomal dysfunction and significant AD-associated decrease in levels of docosahexaenoic acid (DHA)-containing polyunsaturated lipids of different classes, suggesting a potential defect in acyl-chain remodeling. Several immune pathways and senescence were among the top pathways controlled by 4 miRNAs significantly upregulated in the AD group. Our data suggest that loss of the homeostatic microglia signature in late AD stages may accompany endolysosomal impairment and release of undigested neuronal and myelin debris, including tau, through extracellular vesicles. These data validate a method of isolation of small cell-type specific EVs from human brain tissue, suggests new potential EV-associated markers and disease-related pathways, and provides a framework for future large-scale multi-omics study.
HostingRepositoryPRIDE
AnnounceDate2021-11-25
AnnouncementXMLSubmission_2021-11-25_08:36:11.586.xml
DigitalObjectIdentifierhttps://dx.doi.org/10.6019/PXD028898
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportSupported dataset by repository
PrimarySubmitterWhitaker Cohn
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListTMT6plex-126 reporter+balance reagent acylated residue; phosphorylated residue; acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue; deamidated residue
InstrumentOrbitrap Fusion Lumos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02021-10-04 04:43:52ID requested
12021-11-25 08:36:11announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: Alzheimer’s disease, extracellular vesicles, exosomes, microglia, omics analysis
Contact List
Tina Bilousova
contact affiliationDrug Discovery Lab, Department of Neurology, University of California, Los Angeles, CA 90095, USA
contact emailtbilousova@mednet.ucla.edu
lab head
Whitaker Cohn
contact affiliationUniversity of California, Los Angeles
contact emailwhitakercohn@ucla.edu
dataset submitter
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Dataset FTP location
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