The synaptic basis of cognitive reserve in Alzheimer's disease

阿尔茨海默氏病（AD）是一种改变生活和使人衰弱的疾病，其特征在于进行性神经元细胞损失，从而认知能力下降。然而，有趣的是，一些个体被保护免受AD相关的脑蛋白病理（AB和Tau）。这些患者在其大脑中呈现（死后）高病理性蛋白质负荷，而没有相关的记忆丧失和认知能力下降。这表明这些人对AD相关的大脑变化具有认知弹性（CR）。这个博士项目的目的是了解和验证这些人的认知弹性/储备的突触和分子基础（CR个体），目的是了解树突棘和大脑可塑性如何影响神经变性。在项目中，我将使用树突棘数量和形态来研究三个患者组的突触完整性;患者的认知弹性（CR），AD诊断病例和健康（非神经退行性）控制，使我能够确定新的分子标记的CR。该项目将在死后人脑和大鼠脑组织中使用转录组学、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，并研究其在死后人类和大鼠脑组织中的定位。2.从认知弹性（CR）、阿尔茨海默病（AD）和野生型（Wt）非神经退行性患者样本中建立人类转录组学谱。3.建立AD、CR和Wt动物模型，研究在体突触代偿功能。在这些模型中，我们将使用预先确定的（目标1和2）蛋白质和转录组靶点来建立/确认它们与认知恢复力的关系。最终，我们希望描述认知恢复力的特定靶点（生物标志物），这些靶点可能会保护个体免受AD病理学的影响，长期目标是为神经退行性疾病的诊断和治疗提供基于精确医学的医疗保健。

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.