Altered Copper Metabolism as Theranostic Biomarker in Alzheimer's Disease

描述（由申请人提供）：本提案的目的是确定改变的铜代谢作为早期诊断和治疗阿尔茨海默病（AD）的新治疗诊断生物标志物的可行性和用途。铜是哺乳动物必需的营养元素，但过量的铜具有细胞毒性。铜稳态受到铜转运蛋白和分子伴侣的精细网络的严格调节。ATP 7 B基因突变导致Wilson病，这是一种遗传性铜代谢障碍，其特征在于由于肝脏和大脑中过量铜积累的有害影响而引起的肝脏和神经系统症状。新出现的大量证据表明铜代谢改变在AD发病机制中的作用。然而，由于缺乏实时评估体内铜通量的工具，对人脑中的实时铜代谢知之甚少。正电子发射断层扫描（PET）是一种多功能的工具，实时评估铜通量在活的有机体。使用64 CuCl 2作为放射性示踪剂，通过PET/CT证实了Atp 7 b-/-敲除小鼠（威尔逊病的小鼠模型）肝脏中64 C的蓄积增加。我们评估了AD的Tau转基因小鼠模型的脑中的铜代谢，发现Tau Tau-P301 L突变转基因小鼠的脑组织中的64 Cu放射性显著高于正常对照小鼠的脑组织中的64 Cu放射性。我们的初步实验的数据表明，改变铜积累作为一个新的生物标志物的早期诊断AD的PET/CT的潜力。此外，改变的铜代谢具有作为用铜调节疗法早期治疗AD的治疗靶点的潜力。在此，我们提出了纵向评估Tau-P301 L突变转基因小鼠脑铜代谢的年龄依赖性变化的PET/CT使用64 CuCl 2作为放射性示踪剂（64 CuCl 2-PET/CT）。此外，我们将探索改变铜代谢作为Tau-P301 L突变转基因小鼠中铜调节治疗的治疗靶点的潜力。我们这项建议的具体目标是：目标1。采用64 CuCl 2-PET/CT技术对Tau-P301 L突变型转基因小鼠脑内64 Cu放射性随年龄的变化进行纵向评价，探讨铜代谢改变作为AD早期诊断新生物标志物的可行性。目标二：通过使用64 CuCl 2作为放射性示踪剂的microPET/CT和小鼠脑组织中NFT负荷的组织化学分析，监测氯碘喹对Tau-P301 L突变转基因小鼠铜代谢改变和Tau病理学改变的改善的影响，探索铜调节疗法在AD中的治疗潜力。本研究结果有助于阐明铜代谢改变在AD发病机制中的作用，确定64 CuCl 2-PET/CT用于AD早期诊断的可行性，并为进一步研究铜代谢改变作为AD早期治疗靶点提供依据。此外，改变的铜代谢具有作为替代生物标志物的潜力，用于使用64 CuCl 2作为放射性示踪剂通过PET/CT监测靶向tau蛋白病的其他抗AD药物的治疗效果。

DESCRIPTION (provided by applicant): The purpose of this proposal is to determine feasibility and use of altered copper metabolism as a new theranostic biomarker for early diagnosis and treatment of Alzheimer's disease (AD). Copper is an essential nutrient element in mammals, but excess of copper is cytotoxic. Copper homeostasis is tightly regulated by a delicate network of copper transporters and chaperons. Mutation of ATP7B gene causes Wilson's disease, an inherited copper metabolism disorder characterized by hepatic and neurological symptoms due to harmful effect of excess copper accumulation in live and brain. Emerging body of evidence suggests role of altered copper metabolism in pathogenesis of AD. However, little is known about real-time copper metabolism in human brains due to lack of a tool for real-time assessment of copper fluxes in vivo. Positron emission tomography (PET) is a versatile tool for real-time assessment of copper fluxes in live organism. Increased accumulation of 64C was demonstrated in liver of Atp7b -/- knockout mice, a mouse model of Wilson's disease, by PET/CT using 64CuCl2 as a radiotracer. We assessed copper metabolism in brain of Tau transgenic mouse model of AD and discovered that 64Cu radioactivity in brain tissues of Tau Tau- P301L mutant transgenic mice was significantly higher than 64Cu radioactivity in brain tissue of normal control mice. The data of our preliminary experiments suggested potentials of altered copper accumulation as a new biomarker for early diagnosis of AD by PET/CT. Additionally, altered copper metabolism holds potential as a therapeutic target for early treatment of AD with copper modulating therapy. Herein, we propose longitudinal assessment of age-dependent change of copper metabolism in brain of Tau-P301L mutant transgenic mice by PET/CT using 64CuCl2 as a radiotracer (64CuCl2-PET/CT). In addition, we will explore potential of altered copper metabolism as a therapeutic target for copper modulating therapy in Tau-P301L mutant transgenic mice. Our specific aims of this proposal are: Aim 1. To determine the feasibility of altered copper metabolism as a new biomarker for early diagnosis of AD based on longitudinal assessment of age-dependent change of 64Cu radioactivity in brain of Tau-P301L mutant transgenic mice using 64CuCl2 -PET/CT. Aim 2: To explore the therapeutic potentials of copper-modulating therapy in AD by monitoring effects of clioquinol on altered copper metabolism and improvement of Tauopathological changes in Tau-P301L mutant transgenic mice by microPET/CT using 64CuCl2 as a radiotracer and histolochemical analysis of NFT burden in mouse brain tissues. Outcome of this study may shed new light on the role of altered copper metabolism in pathogenesis of AD related to Taupathology, determine feasibility of using 64CuCl2-PET/CT for early diagnosis of AD, and provide evidence to support further study of altered copper metabolism as a therapeutic target for early treatment of AD by copper modulating therapy. Furthermore, altered copper metabolism holds potentials as a surrogate biomarker for monitoring therapeutic effects of other anti-AD drugs targeting tauopathies by PET/CT using 64CuCl2 as a radiotracer.