Naessens Daphne M P, Dobbe Johannes G G, de Vos Judith, VanBavel Ed, Bakker Erik N T P
Department of Biomedical Engineering and Physics, Amsterdam UMC, Amsterdam Neuroscience, University of Amsterdam, Amsterdam, Netherlands.
Department of Biomedical Engineering and Physics, Amsterdam UMC, Amsterdam Movement Sciences, University of Amsterdam, Amsterdam, Netherlands.
Front Neurosci. 2021 Mar 22;15:631325. doi: 10.3389/fnins.2021.631325. eCollection 2021.
The hippocampus is susceptible to protein aggregation in neurodegenerative diseases such as Alzheimer's disease. This protein accumulation is partially attributed to an impaired clearance; however, the removal pathways for fluids and waste products are not fully understood. The aim of this study was therefore to map the clearance pathways from the mouse brain. A mixture of two fluorescently labeled tracers with different molecular weights was infused into the hippocampus. A small subset of mice ( = 3) was sacrificed directly after an infusion period of 10 min to determine dispersion of the tracer due to the infusion, while another group was sacrificed after spreading of the tracers for an additional 80 min ( = 7). Upon sacrifice, mice were frozen and sectioned as a whole by the use of a custom-built automated imaging cryomicrotome. Detailed 3D reconstructions were created to map the tracer spreading. We observed that tracers distributed over the hippocampus and entered adjacent brain structures, such as the cortex and cerebroventricular system. An important clearance pathway was found along the ventral part of the hippocampus and its bordering interpeduncular cistern. From there, tracers left the brain via the subarachnoid spaces in the directions of both the nose and the spinal cord. Although both tracers followed the same route, the small tracer distributed further, implying a major role for diffusion in addition to convection. Taken together, these results reveal an important clearance pathway of solutes from the hippocampus.
海马体在诸如阿尔茨海默病等神经退行性疾病中易受蛋白质聚集影响。这种蛋白质积累部分归因于清除功能受损；然而，液体和废物产物的清除途径尚未完全了解。因此，本研究的目的是绘制小鼠大脑中的清除途径。将两种不同分子量的荧光标记示踪剂混合物注入海马体。一小部分小鼠（n = 3）在注入10分钟后立即处死，以确定由于注入导致的示踪剂扩散情况，而另一组在示踪剂扩散额外80分钟后（n = 7）处死。处死时，将小鼠冷冻并使用定制的自动成像冷冻切片机进行整体切片。创建详细的三维重建以绘制示踪剂扩散情况。我们观察到示踪剂分布在海马体上并进入相邻的脑结构，如皮质和脑室系统。发现一条重要的清除途径沿着海马体的腹侧部分及其相邻的脚间池。从那里，示踪剂通过蛛网膜下腔朝着鼻子和脊髓的方向离开大脑。尽管两种示踪剂遵循相同的途径，但小分子示踪剂分布得更远，这意味着除对流外扩散也起主要作用。综上所述，这些结果揭示了海马体溶质的一条重要清除途径。
