Department of Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, The Netherlands.
Division of Nephrology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Sci Rep. 2017 Apr 7;7(1):744. doi: 10.1038/s41598-017-00861-x.
Hypertension is associated with cognitive decline and various forms of dementia, including Alzheimer's disease. In animal models of hypertension, many of Alzheimer's disease characteristics are recapitulated, including brain atrophy, cognitive decline, amyloid β accumulation and blood brain barrier dysfunction. Removal of amyloid β and other waste products depends in part on clearance via the brain interstitial fluid (ISF). Here we studied the impact of hypertension on ISF drainage, using spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). At 8 months, high (500 kD) and low (3 kD) fluorescent molecular weight tracers released passively into the hippocampus showed a drastically enhanced spreading in SHR. Tracer spreading was inhomogeneous, with accumulation at ISF-CSF borders, around arteries, and towards the stratum lacunosum moleculare. These locations stained positively for the astrocyte marker GFAP, and aquaporin 4. Despite enhanced dispersion, clearance of tracers was not affected in SHR. In conclusion, these data indicate enhanced bulk flow of ISF in the hippocampus of hypertensive rats. ISF drains along astrocytes towards the cerebrospinal fluid compartment, which leads to sieving of high molecular weight solutes. Sieving may lead to a local increase in the concentration of waste products and potentially promotes the aggregation of amyloid β.
高血压与认知能力下降和各种形式的痴呆症有关，包括阿尔茨海默病。在高血压动物模型中，许多阿尔茨海默病的特征得到了再现，包括脑萎缩、认知能力下降、β淀粉样蛋白积累和血脑屏障功能障碍。β淀粉样蛋白和其他废物的清除部分取决于通过脑间质液（ISF）的清除。在这里，我们研究了高血压对 ISF 引流的影响，使用自发性高血压大鼠（SHR）和正常血压的 Wistar Kyoto 大鼠（WKY）。在 8 个月大时，被动释放到海马体中的高（500kD）和低（3kD）荧光分子量示踪剂显示出在 SHR 中明显增强的扩散。示踪剂的扩散不均匀，在 ISF-CSF 边界、动脉周围和向分子层疏松层积聚。这些位置对星形胶质细胞标志物 GFAP 和水通道蛋白 4 呈阳性染色。尽管扩散增强，但 SHR 中的示踪剂清除率没有受到影响。总之，这些数据表明高血压大鼠海马体中 ISF 的整体流动增强。ISF 沿着星形胶质细胞向脑脊液腔引流，导致高分子溶质的筛滤。筛滤可能导致废物浓度在局部增加，并可能促进β淀粉样蛋白的聚集。
