Two diseases, one brain: The effects of cardiovascular disease on the speed, progression and severity of Alzheimer's Disease

到2025年，仅在英国，预计将有超过100万人患有痴呆症，目前还没有有效的治疗方法。最常见的痴呆症是阿尔茨海默病。越来越多的证据表明，在阿尔茨海默病的早期，脑血流量减少，神经血管耦合（调节大脑活跃区域的氧气和葡萄糖供应）功能失调。这种神经血管破裂被认为会导致神经元死亡和认知缺陷。与现有文献相反，我们最近证明，在轻度阿尔茨海默病的临床前模型中，神经血管耦合在疾病发展的关键时间点基本上没有改变。因此，在这种轻度模型中，神经血管缺陷可能比预测的更微妙。在人类阿尔茨海默病中，脑血管和心血管功能障碍常同时发生，但分开治疗。然而，外周血管生理受损可能对中枢神经血管功能有改变作用。在这个项目中，我们将把阿尔茨海默病的临床前模型与一种新的动脉粥样硬化（ATH）模型结合起来，了解心血管疾病如何影响脑血管健康。这一发现将增加我们对神经血管功能障碍如何导致神经退行性疾病以及心血管疾病如何影响阿尔茨海默病进展的认识。为了研究在伴有或不伴有ATH的阿尔茨海默病临床前模型中，神经血管单元的细胞变化在整个生命过程中对阿尔茨海默病病理有何影响，我们将采用高分辨率双光子成像来测量细胞钙和脑血流量。了解在阿尔茨海默病和ATH的新型混合模型中哪些神经血管单元细胞失效，将有可能为人类提供新的治疗靶点。为了评估阿尔茨海默病的进展及其如何受到ATH的影响，认知功能将通过行为测试进行评估，免疫组织化学方法将进一步阐明任何观察到的神经血管功能障碍的病理基础。在攻读博士学位期间，您还将接受数据分析所需的高级计算（例如MATLAB）和统计技能的培训。该项目将进一步了解神经血管功能障碍如何以及何时促进阿尔茨海默病的进展，并将阿尔茨海默病的临床前模型与新型ATH模型相结合，研究心血管疾病如何影响阿尔茨海默病的进展。

By 2025, in the UK alone, over 1 million people are expected to be living with dementia, for which there is currently no effective treatment. The most common dementia is Alzheimer's disease. Growing evidence suggests that early in Alzheimer's disease brain blood flow is reduced and neurovascular coupling - which regulates the supply of oxygen and glucose to active brain regions - is dysfunctional. This neurovascular breakdown has been suggested to lead to neuronal death and cognitive deficits.Contrary to existing literature, we recently demonstrated that neurovascular coupling was largely unaltered at key timepoints in disease development in a mild preclinical model of Alzheimer's disease. In this mild model, therefore, neurovascular deficits may be more subtle than predicted.In human Alzheimer's disease, cerebrovascular and cardiovascular dysfunction often occur together but are treated separately. However, a compromised peripheral vascular physiology may have modifying effects on central neurovascular function. In this project, we will combine pre-clinical models of Alzheimer's disease with a novel model of atherosclerosis (ATH) to understand how cardiovascular disease affects cerebrovascular health. The findings will increase our knowledge of how neurovascular dysfunction contributes to neurodegenerative conditions and how cardiovascular disease might affect the progression of Alzheimer's disease.To investigate which cellular changes in the neurovascular unit contribute to Alzheimer's disease pathology throughout the lifecourse in preclinical models of Alzheimer's disease with and without ATH, we will employ high-resolution 2-photon imaging to measure cellular calcium and cerebral blood flow. Understanding which cells of the neurovascular unit are failing in novel mixed models of Alzheimer's disease and ATH will potentially lead to new therapeutic targets in humans. To assess Alzheimer's disease progression, and how it is impacted by ATH, cognitive function will be assessed with behavioural testing and immunohistochemical approaches will further elucidate pathology underlying any observed neurovascular dysfunction. During the PhD you will also be trained in the advanced computational (e.g. MATLAB) and statistical skills necessary for data analysis.This project will further our understanding of how, and when, neurovascular dysfunction contributes to Alzheimer's disease progression and combine preclinical models of Alzheimer's disease with a novel model of ATH to study how cardiovascular disease might affect Alzheimer's disease progression.