Open AccessEnrichment of Neurodegenerative Microglia Signature in Brain-Derived Extracellular Vesicles Isolated from Alzheimer’s Disease Mouse Models
Author(s) -
Satoshi Muraoka,
Mark P. Jedrychowski,
Naotoshi Iwahara,
Mohammad Abdullah,
Kristen D. Onos,
Kelly J. Keezer,
Jiannan Hu,
Seiko Ikezu,
Gareth R. Howell,
Steven P. Gygi,
Tsuneya Ikezu
Publication year - 2021
Publication title -
journal of proteome research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.644
H-Index - 161
eISSN - 1535-3907
pISSN - 1535-3893
DOI - 10.1021/acs.jproteome.0c00934
Subject(s) - neurodegeneration , microglia , biology , presenilin , astrocyte , neuroinflammation , apolipoprotein e , proteomics , microbiology and biotechnology , extracellular , alzheimer's disease , senile plaques , neuroscience , central nervous system , immunology , pathology , inflammation , biochemistry , medicine , gene , disease
Extracellular vesicles (EVs) are secreted by any neural cells in the central nervous system for molecular clearance, cellular communications, and disease spread in multiple neurodegenerative diseases, including Alzheimer's disease (AD), although their exact molecular mechanism is poorly understood. We hypothesize that high-resolution proteomic profiling of EVs separated from animal models of AD would determine the composition of EV contents and their cellular origin. Here, we examined recently developed transgenic mice (CAST. APP/PS1 ), which express familial AD-linked mutations of amyloid precursor protein ( APP ) and presenilin-1 ( PS1 ) in the CAST/EiJ mouse strain and develop hippocampal neurodegeneration. Quantitative proteomics analysis of EVs separated from CAST. APP/PS1 and age-matched control mice by tandem mass tag-mass spectrometry identified a total of 3444 unique proteins, which are enriched in neuron-, astrocyte-, oligodendrocyte-, and microglia-specific molecules. CAST. APP/PS1 -derived EVs show significant enrichment of Psen1, APP, and Itgax and reduction of Wdr61, Pmpca, Aldh1a2, Calu, Anp32b, Actn4, and Ndufv2 compared to WT-derived EVs, suggesting the involvement of Aβ-processing complex and disease-associated/neurodegenerative microglia (DAM/MGnD) in EV secretion. In addition, Itgax and Apoe, DAM/MGnD markers, in EVs show a positive correlation with Itgax and Apoe mRNA expression from brain tissue in CAST. APP/PS1 mice. These datasets indicate the significant contribution of Aβ plaque and neurodegeneration-induced DAM/MGnD microglia for EV secretion in CAST. APP/PS1 mice and shed light on understanding AD pathogenesis.