posted on 2021-02-03, 20:05authored bySatoshi Muraoka, Mark P. Jedrychowski, Naotoshi Iwahara, Mohammad Abdullah, Kristen D. Onos, Kelly J. Keezer, Jianqiao Hu, Seiko Ikezu, Gareth R. Howell, Steven P. Gygi, Tsuneya Ikezu
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.