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 131I-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.

中文翻译：

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tau在外周的生理清除及其对tauopathies的治疗潜力。

病理性tau蛋白的积累是阿尔茨海默氏病和其他疾病的标志，并且与认知能力下降密切相关。从大脑清除病理性τ是tauopathies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未知。在这里，我们发现大水罐注射了131I标记的合成tau，它从大脑中动态流出，并且主要从小鼠的肾脏，血液和肝脏清除。我们还发现，下腔静脉的血浆tau水平低于人的股动脉。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清除。下一个，我们发现通过腹膜透析降低血液中tau的含量可以降低大脑中的间质液（ISF）的tau含量，并且血液中的tau含量与ISF是动态相关的；此外，在共生模型中增加了另一套外围系统后，大脑的tau外排被加速。最后，我们建立了使用tau转基因小鼠及其野生型同窝动物的共生小鼠模型，发现共生后转基因生物小鼠的脑tau水平和相关病理显着降低，这表明外周tau清除率的长期提高可减轻病理性tau积累和神经退行性变。在大脑中。我们的研究提供了脑部周围病理性tau的生理清除的第一个证据，