Pappolla M A, Matsubara E, Vidal R, Pacheco-Quinto J, Poeggeler B, Zagorski M, Sambamurti K
Department of Neurology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, United States.
Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama, Yufu, Oita 879-5593, Japan.
Curr Alzheimer Res. 2018;15(7):637-642. doi: 10.2174/1567205015666180411092551.
It has been postulated that inadequate clearance of the amyloid β protein (Aβ) plays an important role in the accumulation of Aβ in sporadic late onset Alzheimer's disease (AD). While the blood brain barrier (BBB) has taken the center stage in processes involving Aβ clearance, little information is available about the role of the lymphatic system. We previously reported that Aβ is cleared through the lymphatic system. We now assessed lymphatic Aβ clearance by treating a mouse model of AD amyloidosis with melatonin, an Aβ aggregation inhibitor and immuno-regulatory neurohormone.
To confirm and expand our initial finding that Aβ is cleared through the lymphatic system. Lymphatic clearance of metabolic and cellular "waste" products from the brain into the peripheral lymphatic system has been known for a long time. However, except for our prior report, there is no additional experimental data published about Aβ being cleared into peripheral lymph nodes.
For these experiments, we used a transgenic mouse model (Tg2576) that over-expresses a mutant form of the Aβ precursor protein (APP) in the brain. We examined levels of Aβ in plasma and in lymph nodes of transgenic mice as surrogate markers of vascular and lymphatic clearance, respectively. Aβ levels were also measured in the brain and in multiple tissues.
Clearance of Aβ peptides through the lymphatic system was confirmed in this study. Treatment with melatonin led to the following changes: 1-A statistically significant increase in soluble monomeric Aβ40 and an increasing trend in Aβ42 in cervical and axillary lymph nodes of treated mice. 2- Statistically significant decreases in oligomeric Aβ40 and a decreasing trend Aβ42 in the brain.
The data expands on our prior report that the lymphatic system participates in Aβ clearance from the brain. We propose that abnormalities in Aβ clearance through the lymphatic system may contribute to the development of cerebral amyloidosis. Melatonin and related indole molecules (i.e., indole- 3-propionic acid) are known to inhibit Aβ aggregation although they do not reverse aggregated Aβ or amyloid fibrils. Therefore, these substances should be further explored in prevention trials for delaying the onset of cognitive impairment in high risk populations.
据推测，淀粉样β蛋白（Aβ）清除不足在散发性晚发型阿尔茨海默病（AD）中Aβ的积累过程中起重要作用。虽然血脑屏障（BBB）在涉及Aβ清除的过程中占据核心地位，但关于淋巴系统作用的信息却很少。我们之前报道过Aβ可通过淋巴系统清除。现在我们通过用褪黑素（一种Aβ聚集抑制剂和免疫调节神经激素）处理AD淀粉样变性小鼠模型来评估淋巴系统对Aβ的清除作用。
证实并扩展我们最初的发现，即Aβ可通过淋巴系统清除。大脑中代谢和细胞“废物”产物通过淋巴系统清除到外周淋巴系统这一现象早已为人所知。然而，除了我们之前的报告外，没有关于Aβ被清除到外周淋巴结的其他实验数据发表。
在这些实验中，我们使用了一种转基因小鼠模型（Tg2576），该模型在大脑中过度表达Aβ前体蛋白（APP）的突变形式。我们分别检测转基因小鼠血浆和淋巴结中Aβ的水平，作为血管和淋巴系统清除的替代标志物。同时也检测了大脑和多个组织中的Aβ水平。
本研究证实了Aβ肽可通过淋巴系统清除。褪黑素处理导致了以下变化：1 - 处理组小鼠颈部和腋窝淋巴结中可溶性单体Aβ40有统计学意义的增加，Aβ42有增加趋势。2 - 大脑中寡聚体Aβ40有统计学意义的减少，Aβ42有减少趋势。
这些数据扩展了我们之前的报告，即淋巴系统参与大脑中Aβ的清除。我们认为通过淋巴系统清除Aβ的异常可能导致脑淀粉样变性。已知褪黑素和相关吲哚分子（即吲哚 - 3 - 丙酸）可抑制Aβ聚集，尽管它们不能逆转聚集的Aβ或淀粉样纤维。因此，在高危人群预防认知障碍发病的试验中应进一步探索这些物质。
