A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β.
A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β.
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DOI：
10.1126/scitranslmed.3003748
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发表时间：
2012-08-15
影响因子：
17.1
通讯作者：
Nedergaard M
中科院分区：
文献类型：
--
作者：
Iliff JJ;Wang M;Liao Y;Plogg BA;Peng W;Gundersen GA;Benveniste H;Vates GE;Deane R;Goldman SA;Nagelhus EA;Nedergaard M
由于缺乏淋巴循环，大脑必须通过另一种机制清除细胞外蛋白。脑脊液（CSF）作为脑细胞外溶质的汇，但尚不清楚来自脑实质的溶质如何从脑实质移动到CSF。我们证明了蛛网膜下CSF的相当一部分循环通过脑间质空间。在体内的小荧光示踪剂的双光子成像的基础上，我们表明，CSF进入实质沿着血管旁的空间周围的穿通动脉和脑间质液被清除沿着静脉旁引流途径。星形胶质细胞中缺乏水通道水通道蛋白4（AQP 4）的动物表现出通过该系统的CSF流入减慢，间质溶质清除减少约70%，这表明这些解剖学流入和流出途径之间的大量液体流动得到了星形胶质细胞水运输的支持。被认为在阿尔茨海默病中致病的肽--带荧光素标记的淀粉样蛋白β--沿着沿着这条途径转运，Aqp 4基因的缺失抑制了可溶性淀粉样蛋白β的清除，这表明这条途径可能将淀粉样蛋白β--从中枢神经系统中清除。通过静脉旁血流的清除也可以调节与神经退行性疾病有关的蛋白质的细胞外水平，其损伤可能导致可溶性蛋白质的错误积累。
Because it lacks a lymphatic circulation, the brain must clear extracellular proteins by an alternative mechanism. The cerebrospinal fluid (CSF) functions as a sink for brain extracellular solutes, but it is not clear how solutes from the brain interstitium move from the parenchyma to the CSF. We demonstrate that a substantial portion of subarachnoid CSF cycles through the brain interstitial space. On the basis of in vivo two-photon imaging of small fluorescent tracers, we showed that CSF enters the parenchyma along paravascular spaces that surround penetrating arteries and that brain interstitial fluid is cleared along paravenous drainage pathways. Animals lacking the water channel aquaporin-4 (AQP4) in astrocytes exhibit slowed CSF influx through this system and a ~70% reduction in interstitial solute clearance, suggesting that the bulk fluid flow between these anatomical influx and efflux routes is supported by astrocytic water transport. Fluorescent-tagged amyloid β, a peptide thought to be pathogenic in Alzheimer’s disease, was transported along this route, and deletion of the Aqp4 gene suppressed the clearance of soluble amyloid β, suggesting that this pathway may remove amyloid β from the central nervous system. Clearance through paravenous flow may also regulate extracellular levels of proteins involved with neurodegenerative conditions, its impairment perhaps contributing to the mis-accumulation of soluble proteins.