Deadly Delivery – Microglia May Traffic Tau Via Exosomes

from Alzforum –

Researchers have known for some time that the tau protein wears walking shoes; it can pass between neurons and march across interconnected regions of the brain. Microglial journeymen may facilitate these interneuronal excursions, according to a study published in Nature Neuroscience on October 5. Researchers led by Tsuneya Ikezu at Boston University School of Medicine reported that microglia gobbled up tau from neurons, packaged it into tiny vesicles called exosomes, and spat it out again. Nearby neurons then ingested the cargo. Ridding the mouse brain of microglia or blocking the production of exosomes stymied the spread of tau from the entorhinal cortex to its next-door neighbor, the hippocampus. While other modes of tau transportation may also operate in the brain, the researchers propose that targeting this exosomal intermediary could slow the spread of toxic tau in Alzheimer’s disease. Alzforum first reported on this work from the 2014 Society for Neuroscience annual meeting (see Dec 2014 conference news).

“The findings are quite counterintuitive,” commented Steven Paul of Weill Cornell Medical College, New York, who was not involved in the study. “These results suggest that microglia are the bad actors, as they may be involved in the transmission of tau, rather than the clearance of it.”

exosome rnaDelivery Derailed.

 Phosphorylated tau (red) fails to travel to the granule cell layer in mice treated with an inhibitor of exosome synthesis (bottom panel). Each panel shows (from left to right) the granule cell layer, and the inner and outer molecular layers of the dentate gyrus. [Courtesy of Asai et al., Nature Neuroscience 2015.]

Mounting evidence suggests that aggregated forms of tau spread from one neuron to the next, where they corrupt normal forms of the protein (see June 2009 newsIba et al., 2013). Tau aggregates first appear in the entorhinal cortex in the early stages of AD, and then spread to the hippocampus, where they are thought to damage neurons and cause memory problems (see Braak and Braak, 1991). By using mice in which tau expression is mostly restricted to the EC, researchers have reported that tau can spread across neuronal circuits that connect these two regions (see Feb 2012 news and Apr 2015 news). However, the way tau moves from one neuron to the next is unclear. Furthermore, tau sometimes travels off-road, wandering between neurons that are not connected by synapses.

Exosomes are one vehicle that could theoretically facilitate the transfer of tau along well-worn circuits as well as less-traveled paths. These tiny vesicular packages are released from cells and contain intracellular components. Researchers have detected elevated levels of tau-filled exosomes in the cerebrospinal fluid and blood of people with AD, which suggests that these tau packages are released from cells in the brain (see Saman et al., 2011Fiandaca et al., 2014; and Aug 2014 conference news). While many types of cells, including neurons, can produce exosomes, microglia are the most adept at pumping them out. As the brain’s immune cells, microglia gobble up extracellular material and then either digest it or spit it back out via exosomes.

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Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, Wolozin B, Butovsky O, Kügler S, Ikezu T. (2015) Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci [Epub ahead of print]. [abstract]

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