Effects of repeated low-intensity ultrasound treatment on alpha-synuclein pathology and motor and behavioral outcome in an alpha-synuclein transgenic mouse model

重复低强度超声治疗对 α-突触核蛋白转基因小鼠模型中 α-突触核蛋白病理学以及运动和行为结果的影响

• 批准号: 531992682
• 负责人: Dr. Veronika Purrer
• 金额: --
• 依托单位: Centre for Ageing Dementia Research (CADR)
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/531992682?language=en
• 关键词: Effects; repeated; low; intensity; ultrasound

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the distinct loss of dopaminergic neurons in the substantia nigra. Established underlying pathophysiologic mechanisms include the aggregation of alpha-synuclein (αSyn) and the subsequent formation of intraneuronal inclusions (Lewy bodies, LB). αSyn is implicated in neuronal plasticity and the transport and release of synaptic vesicles. In addition, αSyn levels modulate DA homeostasis through several biochemical pathways. Likely, the balance of soluble and aggregated αSyn is critical for the viability of (dopaminergic) neurons although the precise roles of soluble monomers, oligomers and insoluble, aggregated αSyn remain to be clarified. To date, small prefibrillar oligomers are considered the main neurotoxic culprits and LBs may rather provide a protective mechanism by segregating the toxic oligomeric structures. Current established strategies to treat PD are symptomatic. However, recent research focused on the underlying pathophysiology, e.g. immunotherapies targeting αSyn aggregation and spreading. Nonetheless, a major problem for any compound delivery is the penetration of the blood-brain barrier (BBB), which provides an effective obstacle preventing the passage of 98% of small molecules. Low-intensity focused ultrasound (FUS) is a novel technology that uses acoustic energy to treat defined brain areas without opening the skull. FUS in combination with intravenously injected gas-filled microbubbles (MB) has been used to open the BBB transiently and safely. Thus, PD and other neurodegenerative diseases with protein aggregation, such as Alzheimer’s disease (AD) represent interesting targets for FUS. The Götz laboratory of the Queensland Brain Institute developed a scanning ultrasound approach of FUS (SUS) that allows FUS treatment of the entire mouse brain. Using various modes of ultrasound application, they reported massive clearance of extracellular amyloid-β plaques and intracellular tau fibrils in different AD mouse models. The aim of our project is to investigate the effects of repeated application of various SUS models in transgenic mice overexpressing human wild-type αSyn under control of the murine Thy-1 promoter. In addition to motor and cognitive function, the effects of SUS on the αSyn levels, the formation of oligomers, and aggregation will be assessed in different brain regions and the blood plasma using immunohistochemical and molecular techniques. Further, αSyn-related mechanisms in synaptic function and dopamine homeostasis as well as effects on microglial activation and clearance mechanisms will be investigated. Together, this research may be highly relevant for the therapeutic translation of focused ultrasound and the envisioned application in human PD patients. In addition, the project will provide insights into possible novel approaches to deliver targeted therapies in combination with SUS across the BBB.

帕金森病(PD)是一种进行性神经退行性疾病，其特征是黑质多巴胺能神经元的明显丢失。已建立的潜在病理生理机制包括α-突触核蛋白(α-Syn)的聚集以及随后形成的神经元内包涵体(路易小体，Lb)。α与神经元的可塑性和突触小泡的运输和释放有关。此外，αSYN水平通过几个生化途径调节DA的动态平衡。可溶性和聚集性α突触蛋白的平衡可能对(多巴胺能)神经元的活性至关重要，尽管可溶单体、寡聚体和不可溶的聚集性α突触蛋白的确切作用仍有待阐明。到目前为止，小的前纤维低聚物被认为是神经毒性的主要罪魁祸首，而LBS更可能通过分离有毒的低聚物结构来提供保护机制。目前已建立的治疗帕金森病的策略是有症状的。然而，最近的研究主要集中在潜在的病理生理学上，例如针对αSyn聚集和扩散的免疫治疗。然而，任何化合物输送的一个主要问题是血脑屏障的穿透，它提供了一个有效的障碍，阻止了98%的小分子通过。低强度聚焦超声(FUS)是一种新技术，它使用声能来治疗特定的大脑区域，而不需要打开颅骨。FUS与静脉注射充气微泡(MB)相结合，已被用于瞬时安全地打开BBB。因此，帕金森病和其他具有蛋白质聚集的神经退行性疾病，如阿尔茨海默病(AD)，是FUS有趣的靶点。昆士兰脑研究所的Götz实验室开发了一种FUS(SUS)扫描超声方法，可以对整个小鼠大脑进行FUS治疗。使用不同的超声应用模式，他们报告了在不同的AD小鼠模型中细胞外淀粉样蛋白-β斑块和细胞内tau纤维的大量清除。本课题的目的是研究在小鼠Thy-1启动子的控制下，重复应用不同的SUS模型对过表达人野生型α基因的转基因小鼠的影响。除了运动和认知功能外，还将利用免疫组织化学和分子技术评估超声对不同脑区和血浆中α-Syn水平、寡聚体的形成和聚集的影响。此外，还将探讨α突触功能和多巴胺稳态的相关机制，以及对小胶质细胞激活和清除机制的影响。总之，这项研究可能对聚焦超声的治疗转化和在人类帕金森病患者中的预期应用具有高度的相关性。此外，该项目将提供对可能的新方法的见解，以结合整个BBB的SUS提供靶向治疗。