Editors' ChoiceNeuroscience

Microglia spread tau

Sci. Signal.  10 Nov 2015:
Vol. 8, Issue 402, pp. ec329
DOI: 10.1126/scisignal.aad8159

Microglia, the phagocytic macrophages in the brain, can promote pathological inflammation that contributes to various neurodegenerative diseases. Tau is a microtubule-stabilizing protein and, in the brains of Alzheimer’s disease (AD) patients, aggregates of this protein accumulate intracellularly and extracellularly, where they may activate microglia and promote inflammation. Tau aggregates spread from the entorhinal cortex to the adjacent dentate gyrus and other cortices. Using two mouse models of AD (PS19 or AAV-tau mice), Asai et al. investigated the spread of mutant human tau throughout the brain and found that microglia spread tau aggregates. Comparison of the colocalization of tau with various cell-type and apoptotic markers in either PS19 or AAV-tau mice to that in control mice revealed that microglia phagocytosed mutant tau-bearing neurons that were undergoing apoptosis and that microglia took up more tau protein than did either neurons or astrocytes. Microglial-derived exosomal fractions isolated from PS19 or AAV-tau mice contained tau, but exosomes isolated from neurons or astrocytes from these mice did not. Primary mouse cortical neurons from normal mice accumulated tau from the microglial exosomal fractions, and granule layer cells accumulated injected, labeled tau-containing microglial exosomes. Chemically depleting microglia in vivo reduced the amount of tau found in the dentate gyrus and granule cell layer of AAV-tau mice, and primary neurons accumulated less tau when cultured with exosomes purified from microglia-depleted PS19 mice than with those purified from control mice. Impairing the production of exosome by either knocking down or pharmacologically inhibiting sphingomyelinase-2, the enzyme that synthesizes ceramide for exosome biogenesis, decreased the amount of tau that was released from microglia and transferred to neurons in culture. Injecting AAV-tau and PS19 mice intraperitoneally with a brain-penetrant sphingomyelinase-2 inhibitor (GW4869) decreased the amount of tau found in the granule cell layer, as well as the amount of apoptosis detected therein. The findings indicate that targeting exosomal release from microglia might help delay the spread of pathological tau in AD patients.

H. Asai, S. Ikezu, S. Tsunoda, M. Medalla, J. Luebke, T. Haydar, B. Wolozin, O. Butovsky, S. Kügler, T. Ikezu. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat. Neurosci. 18, 1584–1593 (2015). [PubMed]

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