The synaptic basis of cognitive reserve in Alzheimer's disease

阿尔茨海默病认知储备的突触基础

• 批准号: 2893010
• 金额: --
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2893010
• 关键词: synaptic; basis; cognitive; reserve; Alzheimer

Alzheimer's disease (AD) is a life-changing and debilitating disease characterised by progressive neuronal cell loss and thus, cognitive decline. Interestingly, however, some individuals are protected against AD-associated brain protein pathology (AB and Tau). These patients present (post-mortem) with high-pathological protein burden in their brains, without the associated memory loss and cognitive decline. This suggests these individuals possess cognitive resilience (CR) against AD-associated brain changes. This PhD project aims to understand and characterise the synaptic and molecular basis of cognitive resilience/reserve in these individuals (CR individuals), with the aim to understand how dendritic spine and brain plasticity effects neurodegeneration.During the project I will use dendritic spine number and morphology to investigate synaptic integrity in three patient groups; patients with cognitive resilience (CR), AD-diagnosed cases and healthy (non-neurodegenerative) controls, allowing me to identify novel molecular markers of CR. The project will use transcriptomic, in -vitro and -vivo experiments in post-mortem Human brain and rat brain tissue. The project will have three aims, as follows:1. To establish brain dendritic spine/plasticity-related protein targets and investigate their localisation in post-mortem human and rat brain tissue. 2. To establish human transcriptomic profiles from cognitively resilient (CR), Alzheimer's disease (AD) and wild-type (Wt) non-neurodegenerative patient samples. 3. To establish animal models for AD, CR and Wt, and then to investigate synaptic compensation in vivo. In these models we will then use pre-identified (aims 1 and 2) protein and transcriptomic targets to establish/confirm their relationship to cognitive resilience.Ultimately, we hope to characterize particular targets (biomarkers) for cognitive resilience that may protect individuals from AD-pathology, with a long term goal of providing precision-medicine based healthcare to neurodegenerative diagnosis and treatment.

阿尔茨海默病(AD)是一种改变生活的疾病，以进行性神经细胞丢失为特征，从而导致认知能力下降。然而，有趣的是，一些个体受到保护，免受AD相关脑蛋白病理(AB和Tau)的影响。这些患者(死后)大脑中存在高病理蛋白负担，没有相关的记忆丧失和认知下降。这表明这些人对AD相关的大脑变化具有认知弹性(CR)。本博士项目旨在了解和描述这些个体(CR个体)认知弹性/储备的突触和分子基础，目的是了解树突棘和大脑可塑性如何影响神经退变。在该项目期间，我将使用树突棘数量和形态来研究三组患者：认知弹性(CR)患者、AD诊断病例和健康(非神经退行性)对照组的突触完整性，使我能够识别CR的新分子标记。该项目将在死后的人脑和大鼠脑组织中进行转录、体外和体内实验。该项目将有三个目标，如下：1.建立脑树突棘/可塑性相关蛋白靶点，并研究其在人和大鼠死后脑组织中的定位。2.从认知恢复型(CR)、阿尔茨海默病(AD)和野生型(Wt)非神经退行性疾病患者样本中建立人类转录图谱。3.建立AD、CR和Wt的动物模型，研究其在体内的突触代偿作用。在这些模型中，我们将使用预先识别的(目标1和2)蛋白质和转录目标来建立/确认它们与认知弹性的关系。最终，我们希望表征认知弹性的特定目标(生物标记物)，可能保护个人免受AD病理的影响，长期目标是为神经退行性诊断和治疗提供基于精确医学的医疗保健。