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

项目总结 阿尔茨海默病(AD)是导致痴呆症的最常见原因，影响着数百万人，并构成 给国家带来了严重的财政负担。然而，开发有效的治疗阿尔茨海默病的方法一直是一个挑战。 到目前为止，还没有有效的治疗方法来预防或阻止疾病的发展。一个主要的障碍 因为这是缺乏可靠的治疗目标的疾病。广告与积累 错误折叠的蛋白质包括老年斑(Aβ)和神经原纤维缠结。目前尚不清楚这些因素是如何 蛋白质的蓄积及其在AD发病机制中的作用。此外，AD是一种 在大脑和心脏都有症状的多因素疾病。然而，时间关系 AD的外周症状与发病机制之间的关系尚不清楚。响应NOT-AG-18-051 来自国家老龄研究所，我们建议研究关键的磷调节的作用 蛋白酶体与衰老和阿尔茨海默病具体地说，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残基的Rpn6磷酸化(Ser14-Rpn6磷酸化)， 改变大脑和心脏的衰老过程和AD的发病机制。两个独特的鼠标敲入模型， 将在基线和何时研究Ser14-Rpn6的磷酸化模拟和磷酸化阻断 与AD小鼠模型杂交，产生磷酸化拟态-AD和磷酸化阻断- 广告小鼠。此外，PKA激活蛋白酶体对脑的治疗益处的贡献 和AD动物的心脏，通过一种药物策略，可以增强cAMP/PKA信号和 大脑和心脏中Ser14-Rpn6磷酸化和蛋白酶体活性的增加将被确定。 这项工作将导致对蛋白酶体的一个关键的磷调节的重要机制的洞察。 防止衰老和AD。这项工作的成功还可以促进对 临床上可翻译的疾病治疗策略。

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.