Interstitial fluid drainage is impaired in ischemic stroke and Alzheimer's disease mouse models.
Interstitial fluid drainage is impaired in ischemic stroke and Alzheimer's disease mouse models.
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DOI：
10.1007/s00401-013-1145-2
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发表时间：
2013-09
影响因子：
12.7
通讯作者：
Bacskai BJ
中科院分区：
文献类型：
--
作者：
Arbel-Ornath M;Hudry E;Eikermann-Haerter K;Hou S;Gregory JL;Zhao L;Betensky RA;Frosch MP;Greenberg SM;Bacskai BJ
间质液（ISF）引流途径被认为是脑内溶质和代谢物清除的基础。先前的研究暗示沿动脉的血管周围空间可能是ISF清除的途径，但从未被直接证明。淀粉样蛋白β (Aβ)肽在脑实质中的积累是阿尔茨海默病（AD）的病理标志之一，它可能与肽的产生和清除之间的不平衡有关。沿着血管周围间隙的Aβ引流被认为是介导大脑肽清除的机制之一。因此，我们设计了一种新的方法，利用激光引导的大剂量染料注射和多光子成像，实时观察活体小鼠大脑中的溶质清除。该方法允许高空间和时间分辨率，并揭示了动力学的ISF清除。我们发现ISF沿着动脉和毛细血管的血管周围间隙而不是静脉，并且其清除率呈双指数分布。ISF引流需要一个功能正常的脉管系统，因为当灌注受损时溶质清除率会降低。此外，在血管淀粉样蛋白沉积明显的转基因小鼠中观察到溶质清除率降低；我们认为存在一种前馈机制，通过这种机制，淀粉样蛋白沉积促进淀粉样蛋白进一步沉积。这一重要发现提供了脑血管疾病和阿尔茨海默病之间的机制联系，并提示沿着血管周围途径促进a β清除应被视为AD和CAA治疗方法的新靶点。
The interstitial fluid (ISF) drainage pathway has been hypothesized to underlie the clearance of solutes and metabolites from the brain. Previous work has implicated the perivascular spaces along arteries as the likely route for ISF clearance, however it has never been demonstrated directly. The accumulation of amyloid β (Aβ) peptides in brain parenchyma is one of the pathological hallmarks of Alzheimer disease (AD), and it is likely related to an imbalance between production and clearance of the peptide. Aβ drainage along perivascular spaces has been postulated to be one of the mechanisms that mediates the peptide clearance from the brain. We therefore devised a novel method to visualize solute clearance in real time in the living mouse brain using laser guided bolus dye injections and multiphoton imaging. This methodology allows high spatial and temporal resolution and revealed the kinetics of ISF clearance. We found that the ISF drains along perivascular spaces of arteries and capillaries but not veins, and its clearance exhibits a bi-exponential profile. ISF drainage requires a functional vasculature, as solute clearance decreased when perfusion was impaired. In addition, reduced solute clearance was observed in transgenic mice with significant vascular amyloid deposition; we suggest the existence of a feed-forward mechanism, by which amyloid deposition promotes further amyloid deposition. This important finding provides a mechanistic link between cerebrovascular disease and Alzheimer disease and suggests that facilitation of Aβ clearance along the perivascular pathway should be considered as a new target for therapeutic approaches to AD and CAA.
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影响因子：
4.2
作者：
BURNS, EM;KRUCKEBERG, TW;GAETANO, PK
通讯作者：
GAETANO, PK
影响因子：
17.1
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
通讯作者：
Nedergaard M
影响因子：
4.2
作者：
Launer, Lenore J.;Petrovitch, Helen;White, Lon R.
通讯作者：
White, Lon R.
影响因子：
6.1
作者：
Garcia-Alloza, Monica;Robbins, Elissa M.;Frosch, Matthew P.
通讯作者：
Frosch, Matthew P.
影响因子：
5
作者：
Carare, R. O.;Bernardes-Silva, M.;Weller, R. O.
通讯作者：
Weller, R. O.