Physiological clearance of tau in the periphery and its therapeutic potential for tauopathies
Physiological clearance of tau in the periphery and its therapeutic potential for tauopathies
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外周 tau 蛋白的生理清除及其治疗 tau 蛋白病的潜力
DOI：
10.1007/s00401-018-1891-2
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发表时间：
2018-10-01
影响因子：
12.7
通讯作者：
Wang, Yan-Jiang
中科院分区：
文献类型：
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作者：
Wang, Jun;Jin, Wang-Sheng;Wang, Yan-Jiang
病理性 tau 蛋白的积累是阿尔茨海默病和其他 tau 蛋白病的标志，并且与认知能力下降密切相关。从大脑中清除病理性 tau 蛋白是 tau 蛋白病的主要治疗策略。外周清除脑源性 tau 蛋白的生理能力及其治疗潜力仍然很大程度上未知。在这里，我们发现小脑延髓池注射 I-131 标记的合成 tau 蛋白会动态地从小鼠大脑中流出，并主要从小鼠的肾脏、血液和肝脏中清除；我们还发现，人类下腔静脉中的血浆 tau 水平低于股动脉中的水平。这些发现表明，在生理条件下，tau 蛋白可以流出大脑并在外周被清除。接下来，我们发现通过腹膜透析降低血液中的tau蛋白水平可以降低大脑间质液（ISF）中的tau蛋白水平，并且血液和ISF中的tau蛋白水平呈动态相关；此外，在联体共生模型中添加另一组外周系统后，tau蛋白从大脑的流出加速。最后，我们使用 tau 转基因小鼠及其野生型同窝小鼠建立了联体共生小鼠模型，发现联体转基因小鼠的脑 tau 水平和相关病理在联体共生后显着降低，表明外周 tau 清除的长期增强可减轻大脑中病理性 tau 积累和神经退行性变。我们的研究提供了外周脑源性病理性 tau 蛋白生理清除的第一个证据，表明增强外周 tau 蛋白清除是 tau 病的潜在治疗策略。
Accumulation of pathological tau is the hallmark of Alzheimer's disease and other tauopathies and is closely correlated with cognitive decline. Clearance of pathological tau from the brain is a major therapeutic strategy for tauopathies. The physiological capacity of the periphery to clear brain-derived tau and its therapeutic potential remain largely unknown. Here, we found that cisterna magna injected I-131-labelled synthetic tau dynamically effluxed from the brain and was mainly cleared from the kidney, blood, and liver in mice; we also found that plasma tau levels in inferior vena cava were lower than those in femoral artery in humans. These findings suggest that tau proteins can efflux out of the brain and be cleared in the periphery under physiological conditions. Next, we showed that lowering blood tau levels via peritoneal dialysis could reduce interstitial fluid (ISF) tau levels in the brain, and tau levels in the blood and ISF were dynamically correlated; furthermore, tau efflux from the brain was accelerated after the addition of another set of peripheral system in a parabiosis model. Finally, we established parabiosis mouse models using tau transgenic mice and their wild-type littermates and found that brain tau levels and related pathologies in parabiotic transgenic mice were significantly reduced after parabiosis, suggesting that chronic enhancement of peripheral tau clearance alleviates pathological tau accumulation and neurodegeneration in the brain. Our study provides the first evidence of physiological clearance of brain-derived pathological tau in the periphery, suggesting that enhancing peripheral tau clearance is a potential therapeutic strategy for tauopathies.