Depletion of microglia and inhibition of exosome synthesis halt tau propagation.
Depletion of microglia and inhibition of exosome synthesis halt tau propagation.
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DOI：
10.1038/nn.4132
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发表时间：
2015-11
影响因子：
25
通讯作者：
Ikezu T
中科院分区：
文献类型：
--
作者：
Asai H;Ikezu S;Tsunoda S;Medalla M;Luebke J;Haydar T;Wolozin B;Butovsky O;Kügler S;Ikezu T
病理性tau蛋白的积累是阿尔茨海默病的主要标志。Tau蛋白在疾病早期从内嗅皮层扩散到海马区。小胶质细胞是大脑中的主要吞噬细胞，与tau病理正相关，但它们参与tau传播尚不清楚。我们开发了一种基于腺相关病毒的模型，该模型在4周内表现出从内嗅皮层到齿状回的快速tau传播。我们发现，在这种小鼠模型中，消耗小胶质细胞显著抑制了tau蛋白的传播，并降低了齿状回的兴奋性。此外，我们证明了小胶质细胞通过外泌体分泌来传播tau，并且抑制外泌体合成显著降低了体外和体内的tau传播。这些数据表明，小胶质细胞和外泌体有助于tau蛋白病的进展，外泌体分泌途径可能是治疗靶点。
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.