Massaging brain vessels with vasomotion: Targeting the vasculature to alter disease progression in mouse models of dementia.

我们目前没有治疗方法可以阻止甚至减缓阿尔茨海默病。自20世纪80年代以来，大多数研究都集中在了解大脑中称为β-淀粉样蛋白和Tau蛋白的蛋白质的作用。每个人的大脑中都会产生这些蛋白质，但在健康的人中，它们会从大脑中移除。在阿尔茨海默病中，这些蛋白质的清除出现了问题，它们开始随着时间的推移而积聚。最终，它们会导致脑神经细胞死亡，这就是阿尔茨海默病的症状首次变得明显的时候。尽管有数百万英镑的资金投入到这两种蛋白质的建立和去除它们的方法上，但我们仍然没有一种可以影响疾病速度或结果的治疗方法。最近，关于这种情况的其他理论也开始被研究。其中之一表明，大脑中的血液流动可能是一个重要因素。众所周知，与健康受试者相比，阿尔茨海默氏症患者的大脑中的血流量水平通常较低。一般认为，这是由于大脑中的神经元由于上述蛋白质的积累而死亡。然而，科学家们现在开始研究可能是血流减少导致了这种情况。其中心思想是，血液流动不仅提供能量，而且还有效地清洗大脑产生的所有废物。如果血液流量下降到一定水平以下，可能仅比正常情况低5%或10%，则洗涤效率较低，废物（以蛋白质的形式）积聚。据认为，这些血流变化发生在病情的早期，因此，如果能够开发出一种治疗方法来防止这种血流变化，就可以挽救更大比例的脑细胞。在过去的几年里，我们的研究小组一直在研究患有阿尔茨海默病的小鼠大脑中的血流。这些小鼠是用已知在生命早期患阿尔茨海默氏症的人类中发生的遗传变化饲养的，这种遗传变化被称为家族性阿尔茨海默氏症。这些小鼠过度产生β-淀粉样蛋白，并具有与人类相似的记忆缺陷，并且对于我们的项目至关重要的是，与没有这种情况的动物相比，它们的大脑中的血流量水平较低。该项目的主要目的是通过提高整个基线或引起血流振荡来改变阿尔茨海默病小鼠大脑中的血流。这种振荡被称为血管运动，据信它可能会积极按摩脑血管并改善有毒蛋白质的清除。我们将通过两种不同的方法来改变大脑中的血流。第一种是使用一种称为光遗传学的技术精确激活脑细胞。这种方法的原理是将一种叫做视蛋白的蛋白质插入小鼠大脑中的一种特定神经元中。一旦这些视蛋白到位，我们就可以将蓝光照射到动物的大脑上，使目标细胞变得活跃。我们最近发表的工作和本申请中显示的试验数据表明，刺激这些神经元可显著增加血流量和血管运动。第二种方法被称为高碳酸血症，在这些实验中，小鼠呼吸室内空气，加入少量二氧化碳（5%），这再次被证明可以增加血流量和血管运动。脑血流与神经活动相匹配的机制逐渐崩溃可能是许多脑部疾病的重要原因，甚至可能是正常衰老中出现的认知能力下降。该项目旨在原则上确定增加脑血流量的治疗方法是否可以有效减缓或阻止阿尔茨海默病小鼠模型中阿尔茨海默病相关症状的发展。如果成功，这可能会导致为这种毁灭性疾病开发新的基于血管的疗法。

We currently have no treatment that stops or even slows down Alzheimer's disease. Most research since the 1980's has focussed on understanding the role of proteins in the brain called beta-amyloid and Tau. Everybody produces these proteins in their brains throughout the day, but in healthy people they are removed from the brain. In Alzheimer's disease, something goes wrong with the clearance of these proteins and they start to build up over time. Eventually they cause brain nerve cells to die and this is when the symptoms of Alzheimer's disease first become apparent. Despite millions of pounds in funding being invested into how these two proteins build up and ways to remove them, we still do not have a treatment that can affect disease speed or outcome. Recently, other theories about the condition have started to be investigated. One of these suggests that blood flow in the brain may be an important factor. It is well known that patients with Alzheimer's often have lower levels of blood flow in their brains compared to healthy subjects. It was generally assumed that this was due to neurons in the brain dying because of the build-up of the proteins mentioned above. However, scientists are now starting to investigate the potential that it is the reduction in blood flow that is causing the condition. The central idea is that blood flow not only serves to provide energy but also effectively washes the brain of all the waste it produces. If blood flow drops below a certain level, which may be only 5 or 10% less than normal, the washing is less efficient and the waste (in the form of proteins) builds up. It is thought that these changes in blood flow happen very early in the condition, therefore if a treatment can be developed to prevent this blood flow change, a greater proportion of the brain cells can be saved. For the last few years, our research team has been investigating blood flow in the brains of mice that have Alzheimer's Disease. These mice are bred with genetic changes known to occur in humans who get Alzheimer's very early in life, known as the familial form of the condition. These mice over produce beta-amyloid protein and have similar memory deficits to those seen in humans and, critically for our project, are known to have a lower level of blood flow in their brains compared to animals without the condition. The main aim of this project is to change blood flow in the brains of mice with Alzheimer's disease by either raising the entire baseline or causing blood flow to oscillate. This oscillation is termed vasomotion and it is believed that it might actively massage the brain blood vessels and improve clearance of the toxic proteins. We are going to change blood flow in the brain by two distinct methods. The first is by precise activation of brain cells using a technique called optogenetics. This method works by inserting proteins called opsins into a specific class of neuron in the mouse brain. Once these opsins are in place, we can shine a blue light onto the animal's brain causing the targeted cells to become active. Our recently published work and pilot data shown in this application has shown that stimulation of these neurons robustly increases blood flow and vasomotion. The second method is called hypercapnia, in these experiments the mouse breathes in room air with a small amount of carbon dioxide added (5%), again this has been shown to increase blood flow and vasomotion. A gradual breakdown in the mechanism matching brain blood flow to neural activity may be an important contributory cause of many brain diseases, maybe even the cognitive decline seen in normal aging. The proposed project seeks to establish in principle whether a treatment that increases brain blood flow can effectively slow or block the development of Alzheimer's Disease-associated symptoms in mouse models of the disease. If successful, this could lead to new vascular-based therapies to be developed for this devastating disease.