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

“探索治疗阿尔茨海默病及相关疾病的新疗法” 项目摘要/摘要 神经退行性疾病是突触功能进行性丧失的原因，并伴随着 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 治疗性研究。在阿尔茨海默病(AD)中，被认为是最接近的主要病理标志物 与认知功能障碍有关的是神经原纤维缠结(NFTs)，它由致病聚集体组成 过度磷酸化的tau。为了更好地了解突触丢失和突触损伤之间的病理生理关系 转基因小鼠P301S的AD及相关疾病(ADRD)tau模型的认知功能障碍 过度表达过度磷酸化tau的基因被用于该项目。我在攻读博士后期间完成的工作 研究表明正确的空间和短期识别记忆的下降伴随着 前额叶皮质谷氨酸能受体NMDAR和NMDAR传递的进行性丧失(目标1)。它 怀疑与NFTs发病相关的适应不良的病理生理机制是 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。有缺陷的蛋白质清除一直是 在AD中实施，然而，UPS与tau诱导的认知功能下降有关的作用尚未得到证实 已澄清。进一步的初步数据证实，E3泛素连接酶的上调是 NMDAR的异常降解。在目标2中，我将确定是否选择性地敲除这个E3泛素连接酶 在P301S小鼠的PFC中，通过体内基因转移将挽救突触和认知功能障碍。这将是 通过认知行为分析、生化和免疫细胞化学检测突触进行评估 蛋白质和电生理记录。这些高度可转移的技能将使我转变为一名 博士后任命，我的目标是研究表观遗传酶如何指导染色体结构， 导致神经退行性疾病中出现的基因表达下游变化(目标3)。我的长期生活 我的目标是在一家研究密集型机构获得一个教员职位，在那里我将结合多方面的方法 了解染色质的空间组织如何导致神经生物学和神经退行性变 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.