Impaired activity-dependent protein synthesis in dendrites and pathophysiology in tauopathy

树突活性依赖性蛋白质合成受损和 tau 蛋白病的病理生理学

• 批准号: 10302146
• 负责人: Tara Tracy
• 金额: $ 78.15万
• 依托单位: BUCK INSTITUTE FOR RESEARCH ON AGING
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10302146
• 关键词: Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Biology; Complex; Dementia; Dendrites; Disease; Electrophysiology (science); Eukaryotic Initiation Factors; Event; Foundations; Functional disorder; Genetic Translation; Glutamate Receptor; Goals; Hippocampus (Brain); Human; Impaired cognition; Impairment; Induced pluripotent stem cell derived neurons; Knowledge; Label; Learning; Link; Long-Term Potentiation; Mass Spectrum Analysis; Mediating; Memory; Memory Loss; Memory impairment; Messenger RNA; Methods; Modeling; Molecular; Monitor; Mus; Mutation; Neuronal Plasticity; Neurons; Pathogenicity; Patients; Peptide Initiation Factors; Physiological Processes; Protein Biosynthesis; Protein Dynamics; Proteins; Proteome; Proteomics; Puromycin; Quality of life; Regulation; Research; Ribonucleoproteins; Role; Synapses; Synaptic plasticity; Tauopathies; Therapeutic Intervention; Time; Transgenic Mice; Translating; Translation Initiation; Translations; base; behavior test; density; induced pluripotent stem cell; innovation; knowledge base; mouse model; novel therapeutic intervention; polysome profiling; postsynaptic; response; targeted treatment; tau Proteins; tau mutation; tau-1; therapeutic target; trafficking; translatome

PROJECT SUMMARY/ABSTRACT Pathogenic tau in Alzheimer’s disease and related dementias inhibits the plasticity of neuronal connections underlying progressive memory loss. What remains undetermined, however, are the complex and multifactorial molecular events that disrupt synaptic plasticity in neurons with pathogenic tau. This is major gap in our knowledge of the molecular and physiological processes underlying memory loss in Alzheimer’s disease and related dementias. There is a critical need to uncover how plasticity is dysregulated by pathogenic tau to lay the groundwork for new strategies to target plasticity for therapeutic intervention in these diseases. Long-term potentiation (LTP) is a type of plasticity that involves the persistent strengthening of specific connections between neurons in response to increased activity. There is a strong link between memory impairments and obstructed LTP at synapses in transgenic mouse models of Alzheimer’s disease and related dementias, suggesting that the inability of synapses to express LTP is a key factor leading to memory decline. Our preliminary studies suggest that pathogenic tau blocks the activity-dependent de novo protein synthesis in dendrites that is required for LTP expression. Moreover, we found that pathogenic tau downregulates a translation initiation factor that controls activity-dependent mRNA translation during plasticity. The central hypothesis of this proposal is that pathogenic tau blocks the initiation of local protein translation in dendrites and thereby disrupts the dynamics of postsynaptic proteins that establish LTP and the encoding of new memories. To delineate the mechanism by which pathogenic tau inhibits LTP expression, we propose to use both human induced pluripotent stem cell (iPSC)-derived cultured neurons with familial tau mutations, V337M and R406W, that cause dementia and the PS19 tauopathy mouse model. We will establish the effect of pathogenic tau on the active translation of mRNAs into newly synthesized proteins during LTP expression. We will use a combination of methods to monitor the effect of tau on the rate of protein synthesis and on the subset of mRNAs that are actively translated during LTP. We will next determine the impact of pathogenic tau on a critical step in the initiation of protein translation and the extent to which restoring activity-dependent translation initiation can ameliorate LTP and memory impairments in PS19 mice assessed by electrophysiological recordings and behavioral tests of learning and memory. Finally, we will use an unbiased and innovative APEX proteomics approach to establish the impact of pathogenic tau on the dynamic changes in the postsynaptic protein composition during LTP expression that involve both de novo protein synthesis and the reorganization of protein composition to enhance synaptic strength. From these studies, we expect to elucidate the effect of pathogenic tau on dendritic protein synthesis and the regulation of postsynaptic protein dynamics that underlie the complex and multifactorial causes of memory loss in Alzheimer’s disease and related dementias.

项目摘要/摘要 阿尔茨海默病和相关痴呆的致病tau抑制神经元连接的可塑性 潜在的渐进性记忆丧失。然而，仍未确定的是复杂和多因素的 破坏致病tau神经元突触可塑性的分子事件。这是我们的主要差距 了解阿尔茨海默病记忆丧失的分子和生理过程 相关痴呆症。迫切需要揭示致病tau是如何失调可塑性的，以奠定 为针对这些疾病的治疗干预的可塑性的新战略奠定基础。长期的 增强(LTP)是一种可塑性，它涉及到持续加强特定的连接 神经元对活动增加的反应。在记忆障碍和障碍之间有很强的联系 在阿尔茨海默病和相关痴呆的转基因小鼠模型中突触的LTP，表明 突触不能表达LTP是导致记忆衰退的一个关键因素。我们的初步研究表明 致病tau阻断了LTP所需的树突状细胞中依赖活性的从头蛋白合成。 表情。此外，我们发现致病tau下调了一种控制翻译启动的因子。 可塑性过程中依赖活性的mRNA翻译。这一提议的中心假设是致病的 Tau阻断树突内局部蛋白质翻译的启动，从而扰乱突触后的动力学 建立LTP和编码新记忆的蛋白质。来描述致病机制 Tau抑制LTP的表达，我们建议用人类诱导多能干细胞(IPSC)来源的培养 家族性tau突变神经元，V337M和R406W，导致痴呆和PS19 tau病小鼠 模特。我们将确定致病tau对mrna主动翻译成新合成的mrna的影响。 LTP表达过程中的蛋白质。我们将使用多种方法相结合的方法来监测tau对 蛋白质合成和在LTP过程中被主动翻译的mRNAs的子集。我们接下来将确定 致病tau对蛋白质翻译启动的关键步骤的影响以及在多大程度上 恢复活性依赖的翻译启动可改善PS19小鼠的LTP和记忆障碍 通过电生理记录和学习记忆的行为测试进行评估。最后，我们将使用 一种公正和创新的APEX蛋白质组学方法来确定致病tau对动态的影响 LTP表达过程中突触后蛋白组成的变化 蛋白质成分的合成和重组，以增强突触强度。从这些研究中，我们发现 希望阐明致病tau对树突状细胞蛋白合成和突触后调控的影响 蛋白质动力学是阿尔茨海默病记忆丧失的复杂和多因素原因的基础， 相关痴呆症。