Presenter of 1 Presentation
UNCOVERED PATHOLOGICAL FUNCTION OF PLAQUE ASSOCIATED MICROGLIA WITH HIGHLY TRANSMISSIBLE SECRETORY PROPERTY
Abstract
Aims
We have recently reported that brain-derived extracellular vesicles (BDEVs) from Alzheimer's disease (AD) patients carrying only 300pg of tau propagate tau pathology in aged wild-type mouse brains. To understand BDEV cell types facilitating this phenomenon, we performed quantitative proteomic analysis of BDEVs isolated from AD patients and APP/PS1 mouse brain samples. We further examined EV secretory function of plaque associated microglia in tau propagation mouse model.
Methods
BDEVs were separated from 11 brain samples of AD and control subjects and 6 brain samples of CAST.APP/PS1 and control female mouse at 8 month by discontinuous sucrose gradient ultracentrifugation and subjected to tandem tag mass spectrometry for differentially expressed protein and pathway analysis. Adeno-associated virus containing P301L mutant tau was injected into the entorhinal cortex (EC) of APPNL-G-F mice with or without colony stimulating factor 1 receptor (CSF1R) inhibitor for microglia depletion. Some animals were co-injected with lentivirus to express mEmerald-CD9 specifically in microglia for examining EV secretion in vivo.
Results
Disease associated microglia signature proteins were significantly upregulated in BDEVs with AD patients (APOE, ITGAX and CD63) and APP/PS1 mouse (Itgax) compared to the control. Removal of microglia by CSF1R inhibitor dramatically reduced tau propagation from the EC to the dentate gyrus of hippocampus in APPNL-G-F mouse brains. Interestingly MAC2+ plaque associated microglia secrete significantly more mEmrald+CD9+EVs compared to MAC2- microglia, and possess tau shown by Immuno electron microscope, suggesting pathological tau transfer by those EVs.
Conclusions
Plaque associated microglia may secrete more BDEVs containing tau and may contribute to tau pathology progression in AD.