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）是痴呆症的最常见原因，影响数百万人， 给国家带来沉重的财政负担。然而，开发有效的AD治疗方法一直是一个挑战。 迄今为止，没有有效的治疗方法可以预防这种疾病或阻止其进展。一个主要障碍 这是因为缺乏可靠的治疗靶点。AD与下列物质的积累有关： 包括老年斑（Aβ）和神经纤维缠结在内的错误折叠蛋白。目前尚不清楚这些 蛋白质积累的发生以及它们在AD发病机制中的作用。此外，AD是一种 表现出大脑和心脏症状的多因素疾病。然而，时间关系 外周症状与AD发病机制之间的关系尚不清楚。响应NOT-AG-18-051 来自国家老龄化研究所，我们建议研究一个关键的磷酸调节的作用， 蛋白酶体在衰老和AD中的作用具体来说，我们将确定蛋白酶体功能的变化， 通过增加或减少丝氨酸-14残基处的Rpn 6磷酸化（Ser 14-Rpn 6磷酸化）， 改变大脑和心脏的衰老过程和AD发病机制。两种独特的小鼠基因敲入模型， 将在基线时研究Ser 14-Rpn 6的磷酸化模拟和磷酸化阻断， 与AD小鼠模型杂交以产生磷酸化模拟-AD和磷酸化阻断- AD小鼠。此外，PKA激活蛋白酶体对大脑治疗益处的贡献 和心脏的AD动物施加的药理学策略，可以增加cAMP/PKA信号， 将测定脑和心脏中Ser 14-Rpn 6磷酸化和蛋白酶体活性的增加。 这项工作将导致对蛋白酶体的关键磷酸化调节的重要机制的深入了解， 防止衰老和AD。这项工作的成功也可以促进对一个 临床上可转化的治疗策略。