What goes wrong in Alzheimer's disease? Elucidating pathology-driven synaptic signalling defects in brain circuits. (Project no 2253)

阿尔茨海默病（AD）的标志是正常突触功能的累积失效，这是与灾难性认知衰退相关的事件。然而，人们对造成这种情况的基本事件知之甚少。这种缺乏了解使得确定合适的治疗靶点具有挑战性。一个令人兴奋但在很大程度上未经检验的假设是，AD相关的关键缺陷与含有神经递质的囊泡本身性质的变化有关。突触囊泡是位于突触前末梢特定部位的球状细胞器，负责脑内大部分信息的传递。使用高灵敏度的荧光蛋白和高分辨率相机，我们现在可以直接和动态地跟踪这些囊泡，它们的相关蛋白质和它们促进的发射器释放事件。通过这种方式，有可能对阿尔茨海默病小鼠模型中大脑信号的错误获得重要的新理解。该项目还将利用最先进的高压冷冻技术，该技术允许对突触结构进行非凡的保存，以进行纳米级研究。靶向囊泡池的逻辑建立在我们实验室广泛的高调研究的基础上，这些研究表明，这些是设置和调整突触在基础活动和可塑性中的信号传导特性的关键控制点。在这里，我们假设改变中央和视网膜神经元的特定池属性;它们的大小，它们的物理排列，以及它们在神经元活动期间被使用和重新使用的速度，解释了AD中观察到的关键神经元信号传导缺陷。在这个项目中，您将使用一系列尖端技术，包括光学成像，电生理学和机器学习分析方法，以确定突触是如何出错的。然后，您将测试突触靶向化合物，以尝试恢复功能，从而为疾病治疗提供可能的途径。这个博士学位将为一个有才华的学生提供一个很好的机会，神经科学的职业生涯。

A hallmark of Alzheimer's disease (AD) is the accumulated failure of normal synaptic function, an event associated with catastrophic cognitive decline. However, remarkably little is known about the fundamental events responsible. This lack of understanding makes it challenging to identify suitable therapeutic targets. An exciting but largely untested hypothesis is that key AD-related defects are linked to changes in the properties of the neurotransmitter-containing vesicles themselves. Synaptic vesicles are small spherical organelles organized in clusters at specialized sites in the presynaptic terminal which are responsible for most information transmission in the brain. Using highly-sensitive fluorescent proteins and high-resolution cameras, we can now directly and dynamically track these vesicles, their associated proteins and the transmitter release events that they facilitate. In this way, it is possible to gain significant new understanding of what goes wrong in signalling in the brain in Alzheimer's disease mouse models. The project will also exploit state-of-the-art high-pressure freezing technology that permits extraordinary preservation of synaptic structures for nanoscale investigation. The logic for targeting vesicle pools builds on extensive high-profile research in our lab showing that these are key control points for setting and adjusting the signalling properties of synapses in basal activity and plasticity. Here we hypothesize that changes to specific pool properties in central and retinal neurons; their size, their physical arrangement, and the speed they are used and re-used during neuronal activity, explains key neuronal signalling deficits seen in AD. In this project you will use a range of cutting-edge techniques, including optical imaging, electrophysiology and machine-learning analysis approaches, to identify how synapses go wrong. You will then test synaptically-targeted compounds to try and restore function and therefore offer possible avenues for disease therapy. This PhD will provide a talented student with a great opportunity for a neuroscience career.