Targeting FKBP52 and Copper in Alzheimer's Disease

描述（由申请人提供）：阿尔茨海默病的病理学特征之一是患者大脑中存在神经斑块。这些斑块由淀粉样肽（Ab）的细胞外沉积物组成，周围是营养不良的神经突、反应性星形胶质细胞和小胶质细胞。铜与Ab的相互作用增强了Ab的聚集，诱导了Ab- cu介导的自由基形成和氧化应激的产生。假设ab介导的毒性被细胞外铜增强，并且在AD患者脑脊液中发现铜浓度和铜转运蛋白铜蓝蛋白的增加。这一建议是基于我们最近的观察结果，即亲免疫蛋白FKBP52是哺乳动物细胞中铜外排途径的一个新组成部分，用siRNA或小分子抑制剂下调FKBP52的表达可阻断Atox1-Wilson病蛋白（WDP）铜输出途径的铜外排。因此提出了一个基本问题；FKBP52能否作为控制铜水平和AD进展的治疗靶点？本研究将验证siRNA或靶向亲免疫蛋白的小分子药物可以改善淀粉样变的细胞模型和小鼠APPswe/PS1dE9模型中Ab病理的发展和进化。这项建议旨在解决三个具体问题。

DESCRIPTION (provided by applicant): One of the hallmarks of AD pathology is the presence of neuritic plaques in the brains of afflicted individuals. These plaques are composed of extracellular deposits of amyloid beta peptide (Ab) surrounded by dystrophic neurites, reactive astrocytes, and microglia. The interaction of copper with Ab enhances Ab aggregation and induces the production of Ab-Cu-mediated free radical formation and oxidative stress. It is hypothesized that Ab-mediated toxicity is potentiated by extracellular copper, and increases in the concentration of copper and the copper transport protein ceruloplasmin are found in the CSF of AD patients. This proposal is based on our recent observations that the immunophilin FKBP52 is a novel component of the copper efflux pathway in mammalian cells and down-modulation of FKBP52 expression with siRNA or small molecule inhibitors block copper efflux from the Atox1-Wilson's disease protein (WDP) copper export pathway. The basic question therefore is presented; Can FKBP52 be exploited as a therapeutic target for controlling copper levels and AD progression? This proposal will test the hypothesis that siRNA or small molecule drugs that target the immunophilin will ameliorate the development and evolution of Ab pathology in both cellular models and in a mouse APPswe/PS1dE9 model for amyloidosis. This proposal seeks to address three specific questions. Aim #1. To characterize APP processing, Ab production, and to quantify intracellular copper in cells treated with immunophilin ligands (FK506 or JNJ460) or in FKBP52-downmodulated cells. Aim #2. To determine whether Ab-induced oxidative damage and neurotoxicity is alleviated in FKBP52 down-modulated neuron-glia co-cultures. Aim #3. To investigate if Ab deposition and Ab-mediated synaptic pathology is affected by FKBP52 down-modulation using an inducible mouse model under the control of the tet-off system, and in animals chronically treated with immunophilin ligands (FK506 and JNJ460).