Abeta-mediated toxicity in Alzheimer's disease: delineating mechanisms of internalisation, cell-cell transmission and synaptic dysfunction

阿尔茨海默病（AD）是一种影响1%人口的毁灭性疾病。虽然存在一些家族性AD，但大多数阿尔茨海默病患者患有与衰老相关的散发性迟发性AD。阿尔茨海默病的原因尚不清楚，尽管现在已经确定，在脑细胞（神经元）中，小蛋白（称为Abeta和tau）的异常折叠是疾病病理学的关键步骤。我们的工作旨在了解这些蛋白质如何导致阿尔茨海默氏症患者退行性症状背后的神经功能恶化。为了检验这一点，我们将使用人工生长和天然的活神经元网络，并概括AD发作时发生的变化，因为靶蛋白发生变化并变得有毒。我们将利用最先进的成像方法直接可视化对基本神经元功能的影响。我们的研究还将研究神经元之间有毒蛋白质的传播可能是疾病进展的基础。AD的一个具体后果是突触的逐渐功能障碍-神经元到神经元信号传导的位点-这对大脑处理信息的能力至关重要。我们将使用专门的荧光标记物来检查突触信号事件，并确定被破坏的特定机制。最后，我们将联合收割机将荧光测量与新型最先进的显微镜实验相结合，使我们能够以高分辨率检查由错误折叠蛋白质引起的神经元的详细结构变化。使用这种方法，我们预计主要的新见解，了解与阿尔茨海默病相关的关键细胞和分子变化。有了这些知识，可以靶向这些过程并减轻或预防疾病症状的治疗剂的合理设计成为现实的前景。

Alzheimer's disease (AD) is a devastating illness that affects 1% of the population. Although some familial forms of AD exist, most Alzheimer's patients suffer from sporadic, late-onset AD, associated with ageing. The causes of Alzheimer's disease remain unclear, although it is now well-established that in brain cells (neurons), abnormal folding of small proteins (called Abeta and tau) represents a pivotal step in disease pathology. Our work aims to understand how these proteins can lead to the deterioration of neuronal function underlying the degenerative symptoms seen in Alzheimer's sufferers. To examine this we will use both artificially-grown and native networks of living neurons and recapitulate the changes occurring at the onset of AD as the target proteins change and become toxic. We will utilise state-of-the-art imaging methods to directly visualise the effects on basic neuronal function. Our research will also examine how the spread of toxic proteins between neurons might underlie the progression of the disease. A specific consequence of AD is the gradual dysfunction of synapses - the sites for neuron-to-neuron signalling - that are essential for the brain's ability to process information. We will use specialised fluorescence markers to examine synaptic signalling events and characterise the specific mechanisms which become disrupted. Finally, we will combine our fluorescence measurements with novel state-of-the-art microscopy experiments, allowing us to examine the detailed structural changes in neurons caused by misfolding proteins at high-resolution. Using this approach, we anticipate major new insights into understanding the critical cellular and molecular changes associated with Alzheimer's disease. With this knowledge, the rational design of therapeutic agents that can target these processes and alleviate or prevent disease symptoms becomes a realistic prospect.