Vulnerability of long-range axons in tauopathy

痴呆症，包括阿尔茨海默病，已经是最具破坏性的疾病之一，并将在未来几十年变得更加普遍。目前还没有任何治疗方法可以阻止这种疾病的发展。痴呆症的主要症状包括思维能力的崩溃，比如记忆和解决问题的能力。这些思维能力的丧失是由于大脑内部沟通的中断造成的。这些技能需要仔细协调大脑不同部位的活动。这种不同大脑区域之间的交流是疾病发生时最先受到影响的事情之一。在这项提议中，我们的目标是展示为什么不同大脑区域之间的远程通信被选择性地中断，并利用这些信息开发针对这些早期痴呆阶段的新疗法。大脑不同部分之间的交流依赖于神经细胞或神经元之间传递的信号。为了让一个大脑区域的神经元与另一个大脑区域的神经元直接交流，它有一个很长的突起，叫做轴突，它从神经元的大本营延伸到不同的大脑区域。这个轴突可能需要在大脑内延伸很长的距离，甚至可以直接穿过另一侧到达目标区域。这一提议背后的想法是，在痴呆症的早期阶段，正是这些长轴突容易受到损害。由于这些轴突很长，神经元面临着一个非常棘手的问题，即如何将所有必需的营养物质一直输送到轴突的末端。神经元必须沿轴突向下运输的关键物质之一是线粒体，它为细胞提供能量。它们为轴突提供保持健康的能量，并为其与目标神经元的通信提供动力。这些线粒体像小小的移动发电站一样在轴突内沿着长长的轨道运输。在我们最新的实验中，我们已经看到，如果神经元处于痴呆症的早期阶段，它们的线粒体就不能像正常情况下那样沿着这些轨道行进。我们认为，这可能会给长轴突末端的能量需求带来严重的问题，这可能是为什么这些特别长的轴突发现自己容易受到痴呆症的影响。在这项研究中，我们将把这种断裂的线粒体运输与痴呆期间轴突的损伤联系起来。如果我们的想法是正确的，那么当我们想象远离母区域的轴突时，我们更有可能在看到靠近母区域的轴突之前看到疾病的迹象。为了将这与痴呆症患者大脑活动协调性差联系起来，我们将检查这些长轴突与目标神经元之间的沟通受损。如果这些远程轴突因为运输问题而生病，我们可以利用这些知识来治疗它们。因此，我们将测试加速轴突线粒体运输的药物是否能保护远距离轴突免受疾病的侵害。这将为开发新的痴呆症治疗方法提供概念验证。在这个项目中，至关重要的是我们要看到轴突在大脑中的样子，它们复杂的形状决定了它们与大脑的哪个区域相连。这带来了挑战，因为轴突和它们的线粒体很小，而且它们深埋在大脑内部。为了克服这些挑战，我们将使用一系列尖端的成像技术。第一种方法是使用强大的激光，可以在不损害大脑的情况下对活体大脑深处进行成像。第二种方法使用特殊的化学处理，使大脑变得透明，就像玻璃一样，这样我们就可以通过它成像，揭示里面的轴突。第三种方法使用另一种化学技巧来帮助我们看到微小的线粒体——通过向大脑注入一种膨胀凝胶，我们可以使它们变大。这将使我们能够比以前更详细地了解轴突的内部工作。

Dementia, including Alzheimer's disease, is already one of most devastating illnesses and will get more common over the next few decades. Right now there are no treatments that can stop the disease progressing. The main symptoms of dementia involve the collapse of thinking skills like memory and problem-solving. The loss of these thinking skills is caused by the breakdown of communication within the brain. These skills require the careful coordination of activity in different parts of the brain. This communication between different brain areas is one of the first things affected as the disease takes hold. In this proposal, we aim to show why this long-range communication between different brain regions is selectively disrupted and to use this information to develop new treatments that target these early phases of dementia. Communication between different parts of the brain relies on signals passing between nerve cells, or neurons. To allow a neuron in one brain area to directly communicate with a neuron in another part of the brain, it has a very long protrusion, called its axon, which extends out away from neuron's home location into different brain areas. This axon may have to extend very long distances within the brain, even passing right over to the other side to reach its target area. The idea underlying this proposal is that it is these long axons that are vulnerable to damage in the early stages of dementia. Because these axons are so long, the neurons face a very tricky problem of how to get all the necessary nutrients down all the way to the end of the axons. One of the key things that neurons must transport down their axon are mitochondria, which supply the cell's energy. They provide the energy for the axons to stay healthy and to power communication with its target neurons. These mitochondria are transported like little mobile power stations down long tracks inside the axon. In our latest experiments, we have seen that if neurons are in an early stage of dementia, their mitochondria simply cannot travel down these train tracks as well as they do normally. We believe that this could present serious problems for the energy demands at the end of a long axon and maybe why these particularly long axons find themselves vulnerable to the effects of dementia. In the study, we will link this broken mitochondrial transport to the damage that is done to axons during dementia. If our idea is correct, when we image axons far away from their home area, we are more likely to see signs of sickness before we see it in axons that are close to home. To relate this back to the poor coordination of brain activity seen in dementia patients, we will check for impaired communication between those long axons with their target neurons. If these long-range axons are getting sick because of their transport problems, we can use that knowledge to treat them. As such, we will test if drugs that speed up transport of mitochondria in axons can protect long-range axons from getting sick. This will provide the proof-of-concept for development of new treatments for dementia.In this project, it is crucial that we see the axons as they are in the brain, with their complex shapes that determine which brain areas they connect with. This presents challenges because axons and their mitochondria are tiny, and they are buried deep inside the brain. To overcome these challenges, we will use a collection of cutting-edge imaging techniques. The first of these uses powerful lasers that can image deep inside the living brain without damaging it. The second approach uses special chemical treatments to make the brain transparent, like glass, so we can image through it, revealing the axons inside. The third approach uses another chemical trick to help us see the tiny mitochondria - by infusing an expanding gel into the brain we can make them bigger. This will allow us to see far greater detail about the inner workings of axons than previously possible.