Pathogenic role of novel exosomal protein PRR7 in AD-associated synapse degeneration

新型外泌体蛋白 PRR7 在 AD 相关突触变性中的致病作用

• 批准号: 10458347
• 负责人: Sang H Lee
• 金额: $ 42.9万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10458347
• 关键词: Adult; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid; Amyloid beta-Protein; Biochemical; Biological; Blood; Brain; Cells; Data; Dementia; Development; Disease; Disease Marker; Electrophysiology (science); Event; Excitatory Synapse; Extracellular Space; Functional disorder; Genetic; Goals; Hippocampus (Brain); Human; Impaired cognition; Information Storage; J20 mouse; Knock-out; Knowledge; Maintenance; Mediating; Mediator of activation protein; Memory; Memory Loss; Mission; Molecular; Mus; Neurons; Outcomes Research; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Play; Prevention; Process; Proline; Prosencephalon; Proteins; Public Health; Reporting; Research; Role; Signal Pathway; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Therapeutic Intervention; United States National Institutes of Health; WNT Signaling Pathway; base; cognitive function; design; disability; exosome; experimental study; genetic approach; immunocytochemistry; improved; inhibitor; mouse model; mutant; neurodegenerative dementia; neurofibrillary tangle formation; new therapeutic target; novel; novel diagnostics; novel therapeutic intervention; overexpression; proline-rich proteins; restoration; synaptic function; synaptogenesis; tau Proteins; therapeutically effective

Project Summary Alzheimer’s disease (AD) is a progressive neurodegenerative dementia characterized by decline in memory and cognitive function. Currently there is no effective therapeutic intervention for AD. Synapse loss is one of the invariable pathological features and precedes AD symptom development. Considering that synapses function as fundamental units for information storage in the brain, synapse loss is highly likely to be responsible for the initial memory loss and cognitive decline in AD. Therefore, the prevention of synapse loss and/or restoration of synapse numbers may help improve memory and cognitive function of AD patients. The long term goal is to understand the molecular bases of synapse loss in AD to help develop new therapeutic strategies. Amyloid  (A), a key molecule widely believed to underlie the pathophysiology of AD, is thought to be the main driver for the degeneration and loss of synapses and tau pathology. However, detailed molecular mechanisms by which A elicits synapse loss are not fully understood. Wnt signaling plays an essential role in the formation and maintenance of synapses in the adult brain. Genetic and pathological evidence indicates that dysfunctional Wnt signaling is associated with AD and synapse loss. Proline-rich 7 (PRR7) is a newly identified Wnt inhibitor promoting the weakening and elimination of excitatory synapses. Aberrant expression of PRR7 is implicated in dementia and AD. However, no studies have been performed on the pathogenic role of PRR7 in dementia and AD. Remarkably, we found that central neurons secrete PRR7 to extracellular space via exosomes. PRR7-containing exosomes are subsequently absorbed by surrounding neurons and induces synapse loss in recipient neurons. Therefore, PRR7 has a potential ability to spread synapse loss in the brain under the conditions associated with AD. The central hypothesis of this project is that PRR7 is a critical mediator of the A-induced synapse degeneration in AD. This hypothesis has been formulated based on these findings and preliminary data showing that soluble oligomers of Ainduce the secretion of PRR7 on exosomes. In this project, the involvement of PRR7 in AD-associated synapse loss will be explored by using biochemical, cell biological, and genetic approaches. First, the requirement of PRR7 in A-induced excitatory synapses loss will be studied using cultured hippocampal neurons and an AD mouse model. Second, the role of PRR7-containing exosomes in the spread of synapse degeneration in local neurons will be investigated. The outcome of this research will advance our understanding of the pathogenic synapse loss mechanisms in AD and help design new therapeutic strategy for AD.

项目摘要 阿尔茨海默病(AD)是一种以记忆力下降为特征的进行性神经退行性痴呆 和认知功能。目前对AD尚无有效的治疗干预措施。突触丢失是其中之一 不变的病理特征，并先于AD症状发展。考虑到突触 作为大脑中信息存储的基本单位，突触丢失很可能是 导致阿尔茨海默病最初的记忆丧失和认知能力下降。因此，突触丢失的预防 和/或恢复突触数目可能有助于改善AD患者的记忆和认知功能。这个 长期目标是了解AD突触丢失的分子基础，以帮助开发新的治疗方法 战略。淀粉样蛋白(A)是一种被广泛认为是AD病理生理基础的关键分子，被认为是 是突触退化和丢失和tau病理的主要驱动因素。然而，详细的分子 A引起突触丢失的机制尚不完全清楚。WNT信号在体内起着至关重要的作用 在成人大脑中突触的形成和维持。遗传和病理证据表明 Wnt信号转导功能障碍与AD和突触丢失有关。富含脯氨酸的7(PRR7)是新发现的 WNT抑制剂促进兴奋性突触的减弱和消除。PRR7的异常表达是 与痴呆症和阿尔茨海默病有关。然而，目前还没有关于PRR7致病作用的研究。 痴呆症和阿尔茨海默病。值得注意的是，我们发现中枢神经元通过 外显体。含有PRR7的外切体随后被周围的神经元和诱导物吸收 受体神经元中的突触丢失。因此，PRR7具有在大脑中传播突触丢失的潜在能力 在与AD相关的条件下。这个项目的中心假设是PRR7是一个关键的 A诱导的AD突触变性的介体。这一假说是在这些基础上提出的 研究结果和初步数据表明，A的可溶性寡聚体可诱导PRR7在 外显体。在这个项目中，PRR7在AD相关突触丢失中的作用将通过使用 生物化学、细胞生物学和遗传学方法。首先，PRR7在诱导的兴奋中的需求 突触丢失将使用培养的海马神经元和AD小鼠模型进行研究。二、角色定位 含有PRR7的外切体在局部神经元突触变性扩散中的作用将被研究。这个 这项研究的结果将促进我们对AD致病性突触丢失机制的理解 并帮助设计AD的新治疗策略。