Peng Weiguo, Achariyar Thiyagarajan M, Li Baoman, Liao Yonghong, Mestre Humberto, Hitomi Emi, Regan Sean, Kasper Tristan, Peng Sisi, Ding Fengfei, Benveniste Helene, Nedergaard Maiken, Deane Rashid
Center for Translational Neuromedicine, Division of Glial Disease and Therapeutics, Department of Neurosurgery, University of Rochester Medical Center, Rochester, NY 14642, USA.
Department of Anesthesia, Stony Brook University, Stony Brook, NY, USA; Department of Radiology, Stony Brook University, Stony Brook, NY, USA.
Neurobiol Dis. 2016 Sep;93:215-25. doi: 10.1016/j.nbd.2016.05.015. Epub 2016 May 24.
Glymphatic transport, defined as cerebrospinal fluid (CSF) peri-arterial inflow into brain, and interstitial fluid (ISF) clearance, is reduced in the aging brain. However, it is unclear whether glymphatic transport affects the distribution of soluble Aβ in Alzheimer's disease (AD). In wild type mice, we show that Aβ40 (fluorescently labeled Aβ40 or unlabeled Aβ40), was distributed from CSF to brain, via the peri-arterial space, and associated with neurons. In contrast, Aβ42 was mostly restricted to the peri-arterial space due mainly to its greater propensity to oligomerize when compared to Aβ40. Interestingly, pretreatment with Aβ40 in the CSF, but not Aβ42, reduced CSF transport into brain. In APP/PS1 mice, a model of AD, with and without extensive amyloid-β deposits, glymphatic transport was reduced, due to the accumulation of toxic Aβ species, such as soluble oligomers. CSF-derived Aβ40 co-localizes with existing endogenous vascular and parenchymal amyloid-β plaques, and thus, may contribute to the progression of both cerebral amyloid angiopathy and parenchymal Aβ accumulation. Importantly, glymphatic failure preceded significant amyloid-β deposits, and thus, may be an early biomarker of AD. By extension, restoring glymphatic inflow and ISF clearance are potential therapeutic targets to slow the onset and progression of AD.
类淋巴转运（定义为脑脊液（CSF）沿动脉周围流入脑内以及间质液（ISF）清除）在衰老大脑中会减少。然而，尚不清楚类淋巴转运是否会影响阿尔茨海默病（AD）中可溶性淀粉样蛋白β（Aβ）的分布。在野生型小鼠中，我们发现Aβ40（荧光标记的Aβ40或未标记的Aβ40）通过动脉周围间隙从脑脊液分布到脑内，并与神经元相关。相比之下，Aβ42主要局限于动脉周围间隙，这主要是因为与Aβ40相比，它更容易寡聚。有趣的是，脑脊液中用Aβ40预处理（而非Aβ42）会减少脑脊液向脑内的转运。在有和没有广泛淀粉样蛋白β沉积的AD模型APP/PS1小鼠中，由于有毒Aβ物种（如可溶性寡聚体）的积累，类淋巴转运减少。脑脊液来源的Aβ40与现有的内源性血管和实质淀粉样蛋白β斑块共定位，因此，可能会促进脑淀粉样血管病和实质Aβ积累的进展。重要的是，类淋巴功能障碍先于显著的淀粉样蛋白β沉积出现，因此，可能是AD的早期生物标志物。由此推断，恢复类淋巴流入和ISF清除是延缓AD发病和进展的潜在治疗靶点。
