@article{2a708a8ce3074fc7969b9cf7806827ae,
title = "Depletion of microglia and inhibition of exosome synthesis halt tau propagation",
abstract = "Accumulation of pathological tau protein is a major hallmark of Alzheimer's disease. Tau protein spreads from the entorhinal cortex to the hippocampal region early in the disease. Microglia, the primary phagocytes in the brain, are positively correlated with tau pathology, but their involvement in tau propagation is unknown. We developed an adeno-associated virus-based model exhibiting rapid tau propagation from the entorhinal cortex to the dentate gyrus in 4 weeks. We found that depleting microglia dramatically suppressed the propagation of tau and reduced excitability in the dentate gyrus in this mouse model. Moreover, we demonstrate that microglia spread tau via exosome secretion, and inhibiting exosome synthesis significantly reduced tau propagation in vitro and in vivo. These data suggest that microglia and exosomes contribute to the progression of tauopathy and that the exosome secretion pathway may be a therapeutic target.",
author = "Hirohide Asai and Seiko Ikezu and Satoshi Tsunoda and Maria Medalla and Jennifer Luebke and Tarik Haydar and Benjamin Wolozin and Oleg Butovsky and Sebastian K{\"u}gler and Tsuneya Ikezu",
note = "Funding Information: The authors thank M. Ericsson (Electron Microscopy Facility, Harvard Medical School) for electron microscopic imaging services; P. Davies (Albert Einstein College of Medicine) for providing the MC1, CP13 and PHF1 antibodies; R. Kayed (University of Texas Medical Branch) for providing the T22 polyclonal antibody; Plexxikon, Inc. for providing PLX3397 and control chows; and M. Hasselmo and S. Przedborski for critical reading of the manuscript. This work is supported in part by grants from Alzheimer{\textquoteright}s Association (T.I.), Alzheimer{\textquoteright}s Art Quilt Initiative (T.I.), Boston University Alzheimer{\textquoteright}s Disease Center (P30AG013846, T.I.), BrightFocus Foundation (H.A.) and Coins for Alzheimer{\textquoteright}s Research Trust (T.I.). Publisher Copyright: {\textcopyright} 2015 Nature America, Inc.",
year = "2015",
month = nov,
day = "1",
doi = "10.1038/nn.4132",
language = "English (US)",
volume = "18",
pages = "1584--1593",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "11",
}