Depletion of microglia and inhibition of exosome synthesis halt tau propagation

• DOI: 10.1038/nn.4132
• Publication Date: 2015-10-05T15:39:45Z
• Authors: Hirohide Asai; Seiko Ikezu; Satoshi Tsunoda; Maria Medalla; Jennifer Luebke; Tarik Haydar; Benjamin Wolozin; Oleg Butovsky; Sebastian Kügler; Tsuneya Ikezu
• Keywords: Male; Neurons; 0301 basic medicine; Mice, Transgenic; tau Proteins; Exosomes; Hippocampus; 3. Good health; Disease Models, Animal; 03 medical and health sciences; Alzheimer Disease; Animals; Entorhinal Cortex; Microglia

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.