Cellular and circuit mechanisms of Alzheimer's disease

阿尔茨海默病(AD)是我们社会和医疗保健系统的一颗定时炸弹，随着人口老龄化，预计到2025年，英国将有超过100万人受到影响。这项建议的主要目的是了解为什么神经元和大脑回路在AD中变得功能失调，导致记忆和其他认知能力的毁灭性损害。基因研究清楚地表明，淀粉样β蛋白(Abeta)是这种疾病的驱动力。然而，与因过度表达致病基因(例如突变的淀粉样前体蛋白)而成为AD模型的小鼠形成鲜明对比的是，在数十项大规模临床试验中，阻断或移除Abeta失败，总共涉及数万名患者。也许小鼠模型和阿尔茨海默病患者之间最明显的区别是阿尔茨海默病患者大脑中存在含有tau的神经原纤维缠结。重要的是，每个阿尔茨海默病患者都有tau和abeta。然而，tau对神经回路功能的影响，以及tau和Abeta之间复杂的相互作用，在很大程度上是未知的。在这里，我建议对大型神经元群体进行尖端细胞类型、层和大脑区域特定的体内深度双光子钙成像，以检验以下假设：tau-但不一定是神经纤维缠结-损害新皮质和海马区的神经元活动，并且tau和Abeta之间存在协同作用，加速和恶化损害。我将1)确定导致神经元功能受损的tau的具体类型，并确定其潜在机制，2)在完整神经系统的背景下确定tau和Abeta之间协同作用的机制，以及3)确定细胞特异性损伤对包括睡眠相关的慢波振荡在内的长距离脑回路活动的后果。如果正如我所建议的，阿尔茨海默病患者的神经系统损伤最初依赖于Abeta，但随着tau在大脑中积累，这种依赖变得越来越不那么严重，那么由此得出的结论是，抗Abeta治疗只有在Abeta依赖的初始阶段才有效，这有助于解释为什么后来在疾病中使用的抗Abeta药物的临床试验多次失败。绘制这些阶段的时间和机制图将对指导下一代临床试验具有至关重要的意义；此外，这里提出的高度机械化的实验可能会揭示新的细胞和突触靶点，用于有效的治疗干预，甚至超过Abeta和tau，这是一个关键的未得到满足的临床需求。

Alzheimer's disease (AD) is a ticking time bomb for our society and health care system with populations aging and predictions of over 1 million people affected in the UK by 2025. The overarching aim of this proposal is to understand why neurons and brain circuits become dysfunctional in AD, resulting in devastating impairments of memory and other cognitive abilities. Genetic studies clearly implicate amyloid-beta (Abeta) as a driving force of the disease. However, in sharp contrast to mice that are a model of AD because they overexpress a causative gene (e.g., mutant amyloid precursor protein), blocking or removing Abeta failed in dozens of large-scale clinical trials, involving in total tens of thousands of patients. Perhaps the most obvious difference between the mouse models and Alzheimer patients is the presence of tau-containing neurofibrillary tangles in Alzheimer brains. Importantly, every Alzheimer patient has tau and Abeta. However, the impact of tau on neural circuit function, and the complex interactions among tau and Abeta, are largely unknown. Here I propose to perform cutting-edge cell-type, -layer and brain region-specific in vivo deep two-photon calcium imaging of large neuronal populations to test the hypothesis that tau - but not necessarily neurofibrillary tangles - impairs neuronal activities in neocortex and hippocampus, and that there is synergy between tau and Abeta, accelerating and worsening the impairments. I will 1) determine the specific type of tau causing impaired neuronal function, and identify the underlying mechanisms, 2) determine the mechanisms of the synergistic effects among tau and Abeta in the context of an intact nervous system, and 3) determine the consequences of the cell-specific impairments for long-range brain circuit activities including sleep-related slow-wave oscillations. If, as I propose, neural system impairments in Alzheimer patients start out dependent on Abeta, but become increasingly less so as tau accumulates in the brain, it follows that anti-Abeta treatments would be effective only during the initial Abeta-dependent phase, and help explain the multiple failures of clinical trials of anti-Abeta agents given later in the disease. Mapping the timing and mechanisms of these phases would have crucial importance in informing the next generation of clinical trials; furthermore the highly mechanistic experiments proposed here might reveal novel cellular and synaptic targets for effective therapeutic interventions even beyond Abeta and tau, which is a critical unmet clinical need.