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Nat Neurosci. 2015 Nov;18(11):1584-93. doi: 10.1038/nn.4132. Epub 2015 Oct 5.

Depletion of microglia and inhibition of exosome synthesis halt tau propagation.

Author information

1
Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts, USA.
2
Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts, USA.
3
Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.
4
Alzheimer's Disease Center, Boston University School of Medicine, Boston, Massachusetts, USA.
5
Department of Neurology, Center of Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston University School of Medicine, Boston, Massachusetts, USA.
6
Center of Nanoscale Microscopy and Physiology of the Brain at Department of Neurology, University Medicine Göttingen, Göttingen, Germany.

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.

PMID:
26436904
PMCID:
PMC4694577
DOI:
10.1038/nn.4132
[Indexed for MEDLINE]
Free PMC Article

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