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

项目摘要 阿尔茨海默病（Alzheimer's disease，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。目前尚无有效的治疗措施。突触缺失是 AD的病理特征是不变的，并先于AD症状的发展。考虑到突触 作为大脑中信息存储的基本单位，突触丢失极有可能是 导致AD患者最初的记忆丧失和认知能力下降。因此，防止突触丧失 和/或突触数量的恢复可能有助于改善AD患者的记忆和认知功能。的 长期目标是了解AD中突触丢失的分子基础，以帮助开发新的治疗方法。 战略布局淀粉样蛋白（A β）是广泛认为是AD病理生理基础的关键分子， 是突触和tau病理学的退化和丧失的主要驱动力。然而，详细的分子 A β突触丧失的机制尚未完全了解。Wnt信号传导在 成年人大脑中突触的形成和维持。遗传和病理学证据表明， 功能障碍性Wnt信号传导与AD和突触丧失相关。富含脯氨酸的7（PRR 7）是一种新发现的 促进兴奋性突触减弱和消除的Wnt抑制剂。PRR 7的异常表达是 与痴呆和AD有关然而，还没有对PRR 7的致病作用进行研究， 痴呆和AD。值得注意的是，我们发现，中枢神经元分泌PRR 7到细胞外空间，通过 外来体含有PRR 7的外泌体随后被周围的神经元吸收，并诱导 受体神经元中的突触丧失。因此，PRR 7具有在大脑中传播突触损失的潜在能力 在与AD相关的条件下。该项目的中心假设是PRR 7是一个关键的 AD中A β诱导的突触变性的介质。这一假设是根据这些 研究结果和初步数据显示，可溶性A β寡聚体诱导PRR 7分泌， 外来体在这个项目中，PRR 7参与AD相关的突触丢失将通过使用 生物化学、细胞生物学和遗传学方法。首先，PRR 7在A β诱导的兴奋性细胞中的需要是必需的。 将使用培养的海马神经元和AD小鼠模型研究突触损失。二、作用 将研究含有PRR 7的外泌体在局部神经元中突触变性的扩散中的作用。的 这项研究的结果将促进我们对AD中致病性突触丢失机制的理解 并帮助设计新的AD治疗策略。

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.