Probing prion clearance through interstitial fluid and perivascular pathways

Pron病是一种神经退行性疾病，以快速认知和运动为特征 拒绝。与阿尔茨海默病中的淀粉样蛋白-β类似，某些Pron聚集体通过 并以实质斑块和血管斑块的形式堆积。我们假设普里恩，类似的 对于淀粉样蛋白-β，可以通过间质液体清除血管周围通道。我们 最近发现，缩短小鼠硫酸乙酰肝素链长可减少实质普恩 斑块仍然增加了大脑中的血管斑块，这与Pron清除的改善是一致的 通过间质液体(ISF)。存活时间也延长了。我们和其他人最近也 研究发现，水运输蛋白水通道蛋白4从星形胶质细胞末端的足部重新分布到受普恩病毒影响的血管中，表明在普恩病毒病中血管周围通道发生了变化。此外, 水通道蛋白4在蛋白病中的表达升高。在目标1中，我们将定义时间和方式 在人类Pron病期间，血管通道和血脑屏障发生了改变 老鼠。在目标2中，我们将使用具有CSF-ISF交换受损的遗传小鼠模型来 确定体液交换障碍如何影响Pron疾病进展和表型。我们 也将建立最严重地改变水路运输的Pron构象 蛋白质，脑脊液-间歇性液体交换，以及人类和小鼠的血脑屏障。

Prion diseases are neurodegenerative disorders characterized by rapid cognitive and motor decline. Similar to amyloid-β in Alzheimer’s disease, certain prion aggregates spread through the brain and accumulate as parenchymal and vascular plaques. We hypothesize that prions, similar to amyloid-β, can transit through the interstitial fluid for clearance in perivascular channels. We recently found that shortening heparan sulfate chain length in mice reduced parenchymal prion plaques yet increased vascular plaques in the brain, consistent with improved prion clearance through the interstitial fluid (ISF). Survival time was also prolonged. We and others also recently found that the water transport protein, aquaporin 4, redistributes from astrocyte end feet in prion-affected blood vessels, indicating alterated perivascular channels in prion disease. In addition, aquaporin 4 expression is elevated in prion disease. In Aim 1, we will define when and how vascular channels and the blood brain barrier are modified during prion disease in humans and mice. In Aim 2, we will employ genetic mouse models with impaired CSF-ISF exchange to determine how impairing fluid exchange impacts prion disease progression and phenotype. We will also establish the prion conformers that most severely modify water channel transport proteins, CSF-ISF fluid exchange, and the blood brain barrier in humans and in mice.