The architecture of Alzheimer's disease-associated pathology by cryo-electron tomography

全世界有4700多万人患有痴呆症，其中阿尔茨海默病是最常见的形式。预计到2050年，这一数字将增加到1.3亿以上。由于阿尔茨海默病的发展需要多年的时间，它也给英国带来了巨大的经济和社会负担，其中包括每年260亿英镑的成本。目前，没有可用的治疗方法来预防或减缓这种疾病的进展。阿尔茨海默氏症痴呆症的第一个临床指标是记忆丧失。大脑中神经细胞之间的连接被称为突触，是大脑的微处理器，对我们编码和存储记忆至关重要。在阿尔茨海默病中，突触被一种叫做β -淀粉样蛋白的有缺陷的蛋白质破坏或破坏，这种蛋白质聚集在一起，在大脑中积累。突触的丧失会导致阿尔茨海默病患者的记忆丧失。我的研究旨在了解突触是如何被阿尔茨海默病破坏的，以及这与淀粉样蛋白的积累有何联系。这是通过使用一种称为低温电子显微镜的最新发展方法实现的，这种方法使我们能够非常详细地看到有缺陷的蛋白质，并找出它们是如何破坏突触的。此外，我们已经开发了工作流程，使我们能够将这些成像技术应用于完整的大脑样本，以更好地了解淀粉样蛋白病理内部和周围正在进行的潜在分子和细胞过程，这些淀粉样蛋白病理定义了这种疾病。重要的是，我们能够将这种方法应用于死于这种疾病的阿尔茨海默病患者捐献的死后大脑样本。从这项研究中获得的见解有望揭示新的干预药物靶点，这可能在长期内有助于基于机制的治疗的发展。

More than 47 million people live with dementia worldwide, of which Alzheimer's disease is the most common form. This number is projected to increase to more than 130 million by 2050. Because Alzheimer's disease progresses over many years, it also imposes a large economic and societal burden, including £26 billion cost a year in the UK. Currently, no treatments are available to prevent or slow the progression of this disease. The first clinical indicator of Alzheimer's dementia is the loss of memory. Connections between the nerve cells in the brain, called synapses, are the microprocessors of the mind that are essential for us to be able to encode and store memories. In Alzheimer's disease, synapses are damaged or destroyed by a faulty protein called beta-amyloid that clump together and accumulate in the brain. The loss of synapses contributes to memory loss in people with Alzheimer's disease. My research is aimed at understanding how synapses are damaged by Alzheimer's disease and how this is linked to the accumulation of amyloid. This is achieved by using recent developments in a method called cryo-electron microscopy, which enables us to see the faulty proteins in very high levels of detail and to find out how they damage synapses. In addition, we have developed workflows that allow us to apply these imaging techniques on intact brain samples to better understand the underlying molecular and cellular processes that are ongoing in and around the amyloid pathology that defines this disease. Importantly, we are in a position to apply this approach to postmortem brain samples donated by Alzheimer's patients who have succumbed to the disease. The insights obtained from this research are expected to reveal novel drug targets for intervention that could in the long-term contribute to the development of a mechanism-based therapy.