Depletion of microglia and inhibition of exosome synthesis halt tau propagation

By Hirohide Asai, Seiko Ikezu, S. Tsunoda, Maria Medalla, Jennifer I. Luebke, T. Haydar, B. Wolozin, O. Butovsky, S. Kügler, T. Ikezu. Nature Neuroscience, 2015

1,458 citations recorded by the source corpus.

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.

Subfields: Developmental Neuroscience, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/4f8e43642eadb365b038b2d1260f4be63a859efa

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In Developmental Neuroscience

1. Chao Gao
2. Shengdi Chen
3. Yuyan Tan
4. Jingwen Jiang
5. David V. Hansen

In Neurology

1. Urmi Sengupta
2. J. Long
3. Chao Gao
4. Shengdi Chen
5. Yuyan Tan
6. Jingwen Jiang
7. D. Holtzman
8. Raghu Kalluri

In Physiology

1. J. Long
2. Urmi Sengupta
3. Dominic S A Simpson
4. D. Holtzman
5. P. Oliver
6. Huaxi Xu
7. A. Nilson
8. R. Kayed

Citations in the corpus

• The Role of Amyloid-β Oligomers in Toxicity, Propagation, and Immunotherapy (2016, background): “Tau oligomers are known to spread locally and via synaptic connections (Boluda et al., 2015; Ahmed et al., 2014; Asai et al., 2015).”
• Microglia in Alzheimer’s disease (2018, background): “The interaction of TREM2 with its lipoprotein ligands (LDL, APOE, and CLU) was impaired by the AD-linked mutations of TREM2 (R47H, R62H, and D87N) and completely abolished by Nasu–Hakola disease–linked mutations (Y38C and T66M; Atagi et al., 2015; Bailey et al., 2015; Yeh et al., 2016).”
• Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020, background): “rons or microglia are able to promote tau propagation [250, 251].”
• Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies (2016, background): “Additionally, it appears that microglial cells may facilitate tau propagation by phagocytosis and exocytosis of tau protein [171].”
• Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology. (2016, background): “…elimination can be achieved in the healthy adult mouse brain by treat- ment with small-molecule inhibitors of CSF1R (Elmore et al., 2014; Dagher et al., 2015), with many groups confirming our findings (Valdearcos et al., 2014; Asai et al., 2015; Klein et al., 2015; Schreiner et al., 2015).”
• Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019, positive): “Microglial-derived exosomes appear necessary for tau propagation in a model of tau spreading using AAV viral transduced expression of P301Ltau to induce rapid tau spreading from the entorhinal cortex to the dentate gyrus of the hippocampus (Asai et al., 2015).”
• The biology, function, and biomedical applications of exosomes (2020, positive): “Pathological propagation of Tau aggregation by exosomes was noted in vitro and in vivo (130, 131).”
• Exosome Theranostics: Biology and Translational Medicine (2018, background): “For instance, exosomes derived from primary phagocytes, namely, microglia, contribute to tau propagation, which is associated with Alzheimer’s disease [126].”
• ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020, background): “Similarly, activated microglia are spatially correlated with microtubule-associated protein tau (MAPT, tau) pathology and are capable of recognising and clearing tau [20,21].”
• iPSC-derived human microglia-like cells to study neurological diseases (2017, positive): “…to the acidic lysosomal compartment showing that iMGLs can actively ingest extracellular tau that may be released during neuronal cell death (Villegas-Llerena et al., 2015) and support recent findings that microglia may play a role in tau propagation in AD and other tauopathies (Asai et al., 2015).”