The Role of cAMP/PKA Dysregulation in Aging and the Initial Stages of Alzheimer'sDisease

cAMP/PKA 失调在衰老和阿尔茨海默病初始阶段中的作用

基本信息

批准号：
9911121
负责人：
Shannon Noble Leslie
金额：
$ 2.98万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2021-09-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9911121
关键词：
Adenylate Cyclase Affect Age Age-associated memory impairment Aging Alzheimer&apos s Disease American Animal Model Antibodies Automobile Driving Behavior Biochemical Biological Assay Biometry Brain Calcium Calcium Channel Calcium Signaling Complement Country Cyclic AMP Cyclic AMP-Dependent Protein Kinases Dendritic Spines Development Disease Dissociation Elderly Feedback Human Impaired cognition Inflammatory Late Onset Alzheimer Disease Late-Onset Disorder Lead Left Macaca Mass Spectrum Analysis Measures Mediating Methods Microtubules Mitogen-Activated Protein Kinases Modeling Modification Molecular Molecular Target Monitor Monkeys Neurobiology Neurofibrillary Tangles Pathogenesis Pathologic Pathology Pathway interactions Phosphorylation Phosphotransferases Prefrontal Cortex Prevention strategy Production Protein Kinase Proteins Public Health Rattus Research Risk Risk Factors Rodent Role Ryanodine Receptor Calcium Release Channel Ryanodine Receptors Senile Plaques Signal Pathway Signal Transduction Site Smooth Endoplasmic Reticulum System Therapeutic Training Work age related aged association cortex base career cognitive function cost hyperphosphorylated tau neuroinflammation new therapeutic target novel novel strategies phosphodiesterase 4D phosphoric diester hydrolase prevent protein kinase A kinase tau Proteins tau phosphorylation tau-1 tool

项目摘要

Project Summary/Abstract Late-onset Alzheimer’s disease (LOAD) is a growing public health crisis that already costs our country billions of dollars each year. Currently there are no treatments to slow the progression of LOAD. Age is the largest risk factor for LOAD. There are two key pathological hallmarks of the disease, amyloid beta plaques and neurofibrillary tangles composed of hyperphosphorylated tau. This project focuses on studying the molecular mechanisms by which aging contributes to initial stages of LOAD pathology, particularly tau phosphorylation. To better understand these mechanisms, this project takes advantage of two animal models, aged rats and macaques. Macaques represent a close approximation of the human aging cortex in regards to circuitry and LOAD pathology; however, they are technically challenging. Rats on the other hand do not develop plaques or tangles but do demonstrate age-related cognitive decline and preliminary evidence suggests they present with early stages of tau phosphorylation. Furthermore, rodents provide a breadth of molecular tools to investigate the exact mechanisms by which age-related changes contribute to AD pathology. Previous work from the Nairn and Arnsten labs has demonstrated an increase in cAMP/PKA signaling with age in both of these models, which correlates with tau phosphorylation and cognitive decline. Thus, the proposed project examines the molecular drivers of aberrant cAMP/PKA signaling with age. Aim 1a investigates the role of age-related increases in neuroinflammatory signaling in driving excess cAMP production by removing the brakes, through dysregulation of phosphodiesterases. Aim 1b focuses on the ways in which increases in cAMP/PKA signaling generate a deleterious positive-feedback signaling cascade through phosphorylation of the ryanodine receptor. I plan to investigate how PKA phosphorylation of the ryanodine receptor can increase calcium release from ryanodine receptors and further drive cAMP production. Both of these sub-aims examine the effects of aberrant signaling on PKA phosphorylation of tau and their impact on cognitive decline. Aim 2 expands the scope of these studies through the development of a novel mass spectrometry approach to analyze phosphorylated tau. This novel approach is able to monitor phospho-sites throughout the protein as well as the enrichment of kinase motifs between conditions; thus, enabling a more complete understanding of tau modifications, and the signaling pathways underlying them. Combining this new approach with traditional biochemical assays of tau protein behavior with the use of phosphomimetics, Aim 2 will be able to investigate the important steps by which age-related changes in cAMP/PKA contribute to LOAD tau pathology. Through the aims of this project I will receive extensive training in mass spectrometry, biostatistics, and cortical neurobiology, all of which will prepare me for my desired career in translational neurobiology research. Overall, this project investigates novel molecular targets that represent new therapeutic targets for the treatment of LOAD.

项目概要/摘要晚发性阿尔茨海默病 (LOAD) 是一场日益严重的公共卫生危机，已经给我们的国家带来了损失目前，尚无减缓 LOAD 进展的治疗方法。 LOAD 的最大危险因素该疾病有两个关键的病理特征：β 淀粉样斑块。和由过度磷酸化的 tau 蛋白组成的神经原纤维缠结。衰老导致 LOAD 病理学初始阶段的分子机制，特别是 tau 为了更好地了解这些机制，该项目利用了两种动物模型，老年老鼠和猕猴的大脑皮层与人类衰老的大脑皮层非常相似。电路和负载病理学；然而，另一方面，它们在技术上并不具有挑战性。形成斑块或缠结，但确实表现出与年龄相关的认知能力下降和初步证据表明它们存在早期阶段的 tau 磷酸化。分子工具来研究年龄相关变化导致 AD 病理的确切机制。 Nairn 和 Arnsten 实验室之前的研究表明，cAMP/PKA 信号随着年龄的增长而增加在这两种模型中，这都与 tau 磷酸化和认知能力下降相关。项目检查随年龄变化 cAMP/PKA 信号传导异常的分子驱动因素，目标 1a 研究其作用。年龄相关的神经炎症信号增加通过消除 cAMP 来驱动过量的 cAMP 产生目标 1b 重点关注增加磷酸二酯酶的方式。 cAMP/PKA 信号通过磷酸化产生有害的正反馈信号级联我计划研究兰尼碱受体的 PKA 磷酸化如何增加。兰尼碱受体释放钙并进一步驱动 cAMP 产生，这两个子目标都进行检查。异常信号对 tau 的 PKA 磷酸化的影响及其对认知能力下降的影响。通过开发一种新颖的质谱方法扩大了这些研究的范围分析磷酸化 tau 这种新方法能够监测整个蛋白质的磷酸位点。以及条件之间激酶基序的丰富，从而能够更全面地理解 tau 修饰及其背后的信号通路将这种新方法与传统方法相结合。使用磷酸模拟物对 tau 蛋白行为进行生化分析，Aim 2 将能够进行研究 cAMP/PKA 中与年龄相关的变化导致 LOAD tau 病理学的重要步骤。该项目的目标我将接受质谱、生物统计学和皮质方面的广泛培训神经生物学，所有这些都将为我从事转化神经生物学研究的理想职业做好准备。该项目研究代表治疗以下疾病的新治疗靶点的新分子靶点加载。