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

点击翻译按钮获取中文摘要

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.