Exploration of a Novel Therapeutic for Alzheimer's Disease and Related Disorders

“探索阿尔茨海默病及相关疾病的新疗法” 项目总结/摘要 神经退行性疾病是突触功能进行性丧失的原因， 认知能力下降这些疾病的病理特征影响功能的机制 认知过程，如记忆识别，计划和决策，是一个主要的焦点， 治疗研究在阿尔茨海默病（AD）中，被认为与阿尔茨海默病（AD）最密切相关的主要病理标志物是 与认知功能障碍相关的是神经元缠结（NFT），其由致病性聚集体组成 过度磷酸化的tau蛋白为了更好地理解突触丢失和突触后膜损伤之间的病理生理学关系， AD和相关疾病（ADRD）的tau模型中的认知功能障碍，转基因小鼠模型P301 S 其过表达过度磷酸化的tau蛋白。我在读博士前所做的工作 研究表明，伴随着大脑的衰老， 前额叶皮层中的多巴胺能受体NMDAR和NMDAR传递的进行性损失（Aim 1）。它 怀疑与NFT发作相关的适应不良病理生理机制是 导致突触和认知功能障碍一个感兴趣的领域是泛素-蛋白酶体系统（UPS）， 负责细胞内蛋白质降解的清除机制。蛋白质清除缺陷 在AD中实施，然而UPS与tau诱导的认知下降相关的作用尚未被证实。 阐明。进一步的初步数据表明，E3泛素连接酶的上调是导致 NMDAR的异常降解。在目标2中，我将确定是否选择性地敲低E3泛素连接酶 在PFC的P301 S小鼠通过体内基因转移将拯救突触和认知功能障碍。这将是 通过认知行为测定、突触的生物化学和免疫细胞化学检测来评估 蛋白质和电生理记录。这些高度可转移的技能将使我能够过渡到一个 博士后任命，在那里我的目标是研究表观遗传酶如何指导染色体结构， 引起神经变性疾病中基因表达的下游变化（目的3）。我的长期 我的目标是在一个研究密集型机构获得一个教职，在那里我将联合收割机结合多方面的方法 在理解染色质的空间组织如何导致神经生物学和神经退行性疾病方面， 病因学

“Exploration of a Novel Therapeutic for Alzheimer’s Disease and Related Disorders” Project Summary / Abstract Neurodegenerative disorders are responsible for progressive loss of synaptic function that is accompanied by cognitive decline. The mechanisms in which pathological hallmarks of these diseases influence the functioning of cognitive processes such as memory recognition, planning, and decision making, is a major focus for therapeutic research. In Alzheimer’s disease (AD), the primary pathological marker thought to be most closely linked to cognitive dysfunction is neurofibrillary tangles (NFTs), which are comprised of pathogenic aggregates of hyperphosphorylated tau. To better understand the pathophysiological relationship between synaptic loss and cognitive dysfunction in a tau model for AD and related disorders (ADRD), the transgenic mouse model P301S which overexpresses hyperphosphorylated tau was employed for this project. Work done during my predoctoral studies revealed a decline of proper spatial and short-term recognition memory that is accompanied by the progressive loss of the glutamatergic receptor NMDAR and NMDAR transmission in prefrontal cortex (Aim 1). It is suspected that maladaptive pathophysiological mechanisms associated with the onset of NFTs are responsible for synaptic and cognitive dysfunction. An area of interest is the ubiquitin-proteasome system (UPS), a clearance mechanism responsible for protein degradation in the cell. Defective protein clearance has been implemented in AD, however the role in which the UPS relates to tau-induced cognitive decline has yet to be elucidated. Further preliminary data identified the upregulation of an E3 ubiquitin ligase to be responsible abnormal degradation of NMDARs. In Aim 2 I will determine if selectively knocking down this E3 ubiquitin ligase in PFC of P301S mice through in vivo gene transfer will rescue synaptic and cognitive dysfunction. This will be assessed through cognitive behavioral assays, biochemical and immunocytochemical detection of synaptic proteins, and electrophysiological recordings. These highly transferable skills will allow me to transition into a postdoctoral appointment, where I aim to study how epigenetic enzymes direct chromosomal architecture, causing downstream changes in gene expression seen in neurodegenerative disorders (Aim 3). My long-term goal is to obtain a faculty position at a research-intensive institution where I will combine a multifaceted approach in understanding how the spatial organization of chromatin can lead to neurobiological and neurodegenerative etiologies.