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

• 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
• 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' 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

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.

项目摘要/摘要 迟到的阿尔茨海默氏病（负载）是日益增长的公共卫生危机，已经使我们的国家损失了 每年数十亿美元。当前没有治疗方法可以减慢负载的进展。年龄是 负载的最大风险因素。该疾病有两个关键的病理标志，淀粉样蛋白β斑块 和由高磷酸化tau组成的神经纤维缠结。该项目着重于研究 衰老有助于负荷病理学的初始阶段的分子机制，尤其是tau 磷酸化。为了更好地了解这些机制，该项目利用了两个动​​物模型， 老鼠和猕猴。猕猴代表人类衰老皮层的近似 电路和负荷病理；但是，它们在技术上受到挑战。另一方面，老鼠没有 发展斑块或缠结，但确实证明了与年龄有关的认知能力下降和初步证据 表明它们具有tau磷酸化的早期阶段。此外，啮齿动物提供了广度 分子工具研究了与年龄相关的变化有助于AD病理学的确切机制。 Nairn和Arnsten Labs的先前工作表明，随着年龄的增长，CAMP/PKA信号的增加 在这两个模型中，与Tau磷酸化和认知能力下降相关。那，提议 项目考试随着年龄的增长而异常营地/PKA信号的分子驱动器。 AIM 1A调查角色 通过去除驾驶中与年龄相关的神经炎症信号的增加超过了营地产量 制动器，通过磷酸二酯酶的失调。 AIM 1B专注于增加的方式 CAMP/PKA信号通过通过磷酸化产生有害的正反馈信号级联 ryanodine受体。我计划研究ryanodine受体的PKA磷酸化如何增加 钙从ryanodine受体中释放，并进一步推动营地生产。这两个子ims检查 异常信号传导对TAU的PKA磷酸化及其对认知能力下降的影响。目标2 通过开发一种新型的质谱方法来扩大这些研究的范围 分析磷酸化的tau。这种新颖的方法能够在整个蛋白质中监测磷酸一点 以及条件之间的激酶基序的富集；因此，使人们对 Tau修改以及它们为其底部的信号通路。将这种新方法与传统方法相结合 tau蛋白行为的生化测定通过使用磷光学，AIM 2能够研究 与年龄相关的CAMP/PKA变化有助于负载TAU病理学的重要步骤。通过 该项目的目的我将获得质谱，生物统计学和皮质的广泛培训 神经生物学，所有这些都将为我为转化神经生物学研究的理想职业做好准备。全面的， 该项目研究了代表新的治疗靶标的新型分子靶标 加载。