Priming the proteasome to protect against aging and Alzheimer's disease

启动蛋白酶体以预防衰老和阿尔茨海默病

• 批准号: 10448146
• 负责人: XUEJUN WANG
• 金额: $ 162.59万
• 依托单位: UNIVERSITY OF SOUTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10448146
• 关键词: 26S proteasome; Adenylate Cyclase; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease therapeutic; Animal Diseases; Attention; Brain; Brain Diseases; Cause of Death; Cessation of life; Characteristics; Closure by clamp; Cognitive; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Dementia; Deterioration; Development; Disease; Disease Progression; Exhibits; Financial Hardship; Forskolin; Functional disorder; Genes; Genetic; Heart; Heart Diseases; Heart failure; Hippocampus (Brain); Impairment; Knock-in; Knock-in Mouse; Learning; Link; Longevity; Mediating; Memory Loss; Memory impairment; Methods; Modeling; Molecular; Mus; Mutant Strains Mice; Mutate; Mutation; Myocardial dysfunction; National Institute on Aging; Neurofibrillary Tangles; Neurons; Organ; Pathogenesis; Pathology; Peripheral; Persons; Pharmaceutical Preparations; Pharmacology; Phosphorylation; Physiological; Pilot Projects; Play; Process; Protein Kinase; Proteins; Quality Control; Reporter; Reporting; Research; Risk Factors; Role; Rolipram; Senile Plaques; Serine; Signal Transduction; Symptoms; System; Testing; Therapeutic; Time; Ubiquitin; Ubiquitin Like Proteins; United States; Work; aging brain; brain cell; brain dysfunction; clinically translatable; cognitive function; defined contribution; design; effective therapy; familial Alzheimer disease; human old age (65+); inhibitor; innovation; insight; middle age; mimicry; misfolded protein; mouse model; multicatalytic endopeptidase complex; neurobiological mechanism; overexpression; particle; phosphodiesterase IV; prevent; protein activation; protein degradation; proteostasis; response; success; therapeutic target; therapeutically effective

PROJECT SUMMARY Alzheimer’s disease (AD) is the most common cause of dementia that affects million people and poses a serious financial burden to the nation. However, to develop effective therapeutics for AD has been a challenge. To date, no effective treatment is available to either prevent the disease or halt its progression. A major hurdle for this is the lack of reliable therapeutic targets for the disease. AD is associated with accumulation of misfolded proteins including senile (Aβ) plaques and neurofibrillary tangles. It remains unclear how these protein accumulations occur and what roles they play in the pathogenesis of AD. Additionally, AD is a multifactorial disease exhibiting symptoms both in the brain and heart. However, the temporal relationship between the peripheral symptoms to AD pathogenesis remains unknown. In response to the NOT-AG-18-051 from the National Institute on Aging, we propose to study the role of a key phosphoregulation of the proteasome in aging and AD. Specifically, we will determine whether changes in proteasome functionality, through increase or decrease of Rpn6 phosphorylation at the serine-14 residue (Ser14-Rpn6 phosphorylation), alter aging process and AD pathogenesis in both the brain and heart. Two unique mouse knock-in models, phosphorylation mimicry and phosphorylation blockade at Ser14-Rpn6, will be studied at baseline and when crossed with an AD mouse model to generate the phosphorylation mimicry-AD and phosphorylation blockade- AD mice. Furthermore, the contribution of proteasome activation by PKA to the therapeutic benefits to the brain and heart of AD animals exerted by a pharmacological strategy that can augment cAMP/PKA signaling and increase Ser14-Rpn6 phosphorylation and proteasome activities in both the brain and heart will be determined. This work will lead to significant mechanistic insight into a key phosphoregulation of the proteasome in protection against aging and AD. Success of this work can also advance the mechanistic understanding of a clinically translatable therapeutic strategy for the disease.

项目摘要 阿尔茨海默氏病（AD）是影响百万人的痴呆症最常见的原因 严重的金融伯恩伯恩（Burnen）。但是，开发有效的AD疗法是一个挑战。 迄今为止，尚无有效的治疗方法可以防止疾病或停止其进展。一个重大障碍 因为这是缺乏可靠的疾病治疗靶标。广告与积累有关 错误折叠的蛋白质包括老年（Aβ）斑块和神经纤维缠结。目前尚不清楚如何 蛋白质积累发生以及它们在AD发病机理中起什么作用。另外，广告是 多因素疾病在大脑和心脏中都表现出症状。但是，临时关系 在AD发病机理的周围症状之间仍然未知。响应非AG-18-051 从国家衰老研究所（National Institute 衰老和AD中的蛋白酶体。具体而言，我们将确定蛋白酶体功能的变化是否 通过增加或减少丝氨酸-14居住（Ser14-RPN6磷酸化）处的RPN6磷酸化，， 改变大脑和心脏的衰老过程和AD发病机理。两个独特的鼠标敲入模型， Ser14-RPN6处的磷酸化模拟和磷酸化阻滞将在基线时进行研究 与AD小鼠模型交叉以产生磷酸化模拟AD和磷酸化阻滞 - AD小鼠。此外，PKA激活蛋白酶体对大脑的治疗益处的贡献 和通过药物策略施加的广告动物的心脏，该策略可以增加营地/PKA信号传导和 将确定大脑和心脏中的Ser14-RPN6磷酸化和蛋白酶体活性。 这项工作将导致对蛋白酶体关键磷酸调节的重要机理洞察力 防止衰老和广告。这项工作的成功也可以提高对 该疾病的临床翻译治疗策略。