Cellular and circuit mechanisms of Alzheimer's disease

阿尔茨海默病(AD)是我们这个时代的公共卫生和科学挑战。这种疾病的特征是大脑中存在Abeta和tau蛋白的异常沉积，以及对学习、记忆和认知至关重要的区域神经细胞的丢失。我工作的总体目标是了解为什么神经细胞及其所在的大脑网络在阿尔茨海默病中出现故障，并导致患者的思维、行为和感觉方式发生悲剧性变化。为了追求这一目标，我的研究员迄今对阿尔茨海默病患者大脑中积累的有毒蛋白质如何影响特定的脑细胞和网络提出了重要的见解，这为潜在的治疗开辟了新的靶点。作为这项工作的一部分，我的实验室已经建立了最先进的工具，可以非常高精度地记录脑细胞和网络活动，现在可以用来研究脑细胞和网络如何跨越大脑的遥远区域相互作用，包括那些位于大脑深处的区域，这些区域传统上很难与浅层区域同时到达和记录。这一点很重要，因为最近的研究表明，大脑更深层的区域也显示出有毒蛋白质的积聚，在阿尔茨海默病中以不同的方式进行交流，并且越来越多地被认为在塑造记忆等心理能力方面发挥着关键作用。为了在我过去三年工作的基础上再接再厉，这次奖学金续期建议利用和进一步开发这些技术，并在疾病模型中收集尖端实验数据，从而建立一个脑细胞和网络如何受到AD影响的全脑模型。这项研究将极大地推进我们对整个AD大脑的微观变化的理解，例如有毒蛋白质的积累及其对脑细胞的影响，以及如何将其与“现实世界”水平的变化联系在一起，例如记忆力低下和行为改变，目前尚不清楚。这具有相当大的潜力，可以提供急需的疾病阶段标记和治疗结果的敏感读数，以便在正确的时间向正确的患者提供治疗，并根据他们为患者带来有意义的现实世界好处的能力进行判断。因此，这项工作将借鉴和建立在我的实验室最近取得的重大知识和技术进步的基础上。这将使我的研究向前迈进一大步，了解AD对整个大脑的影响，并导致解决这种毁灭性和过于常见的疾病所迫切需要的重要结果。

Alzheimer's disease (AD) is the public health and scientific challenge of our age. The disease is characterised by the presence of abnormal deposits of Abeta and tau proteins in the brain and a loss of nerve cells in regions critical for learning, memory and cognition. The overall aim of my work is to understand why nerve cells, and the brain networks in which they reside, become faulty in AD and lead to tragic changes in how patients are able to think, act and feel.In pursuit of this aim, my fellowship has thus far led to important insights into how toxic proteins that build up in the brains of AD patients affect specific brain cells and networks, and this has opened up new targets for potential treatments. As part of this, my laboratory has established state-of-the-art tools that allow recordings of brain cell and network activity with very high precision, and which can now be used to study how brain cells and networks interact across distant regions of the brain, including those located deep in the brain which have been traditionally difficult to reach and record at the same time as those in shallower locations. This is important, as recent work has suggested that deeper brain regions also show the build-up of toxic proteins, communicate differently in AD, and are ever more thought to play a key role in shaping mental abilities such as memory. In order to build on my work over the last three years, this fellowship renewal proposes to exploit and further develop these technologies and gather cutting-edge experimental data in disease models that will allow a brain-wide model of how brain cells and networks are affected by AD. This research will significantly move forward our understanding of how microscopic changes across the AD brain, such as the build-up of toxic proteins and their effect on brain cells, are linked to changes at the 'real-world' level, such as poor memory and altered behaviour, which is currently unclear. This has the considerable potential to offer much needed signatures of disease stage and sensitive read-outs of treatment outcomes, so that treatments can be given at the right time to the right patients and judged on their ability to bring about meaningful real-world benefits to the patient. This work will therefore draw and build upon the significant knowledge and technical advances recently made in my laboratory. It will allow my research to take the next major step forward to understand the impact of AD on the whole brain and lead to important outcomes that are urgently required to tackle this devastating and all too common disease.