Targeting FKBP52 and Copper in Alzheimer's Disease

靶向 FKBP52 和铜治疗阿尔茨海默病

• 批准号: 7150136
• 负责人: RAYMOND B BIRGE
• 金额: $ 19.13万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7150136
• 关键词: Alzheimer' s disease; amyloid proteins; amyloidosis; copper; drug discovery /isolation; gene induction /repression; genetic operator element; genetically modified animals; glia; intracellular transport; laboratory mouse; ligands; mixed tissue /cell culture; neurons; neuropathology; neurotoxicology; oxidative stress; pathologic process; peptidylprolyl isomerase; protein biosynthesis; small interfering RNA; small molecule; tetracyclines

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).

描述（由申请人提供）：AD病理学的标志之一是在患病个体的脑中存在神经炎斑块。这些斑块由淀粉样β肽（Ab）的细胞外沉积物组成，所述淀粉样β肽（Ab）被营养不良的神经突、反应性星形胶质细胞和小胶质细胞包围。铜与Ab的相互作用增强Ab聚集，并诱导产生Ab-Cu介导的自由基形成和氧化应激。据推测，抗体介导的毒性是由细胞外铜增强，并在铜和铜转运蛋白铜蓝蛋白的浓度增加被发现在AD患者的CSF中。该提议基于我们最近的观察，即亲免素FKBP 52是哺乳动物细胞中铜流出途径的新组分，并且用siRNA或小分子抑制剂下调FKBP 52表达阻断了Atox 1-Wilson病蛋白（WDP）铜输出途径的铜流出。因此，提出了一个基本问题：FKBP 52能否作为控制铜水平和AD进展的治疗靶点？该提议将检验这样的假设，即靶向亲免蛋白的siRNA或小分子药物将改善淀粉样变性的细胞模型和小鼠APPswe/PS1 dE 9模型中Ab病理的发展和演变。这项建议旨在解决三个具体问题。 目标1。表征APP加工、Ab产生，并定量亲免蛋白配体（FK 506或JNJ 460）处理的细胞或FKBP 52下调细胞中的细胞内铜。 目标2。确定在FKBP 52下调的神经元-神经胶质细胞共培养物中Ab诱导的氧化损伤和神经毒性是否减轻。 目标3。使用tet-off系统控制下的诱导型小鼠模型和长期接受亲免素配体（FK 506和JNJ 460）治疗的动物，研究Ab沉积和Ab介导的突触病理是否受到FKBP 52下调的影响。