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受苦个体的大脑中存在神经斑块。这些斑块由淀粉样蛋白β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聚集，并诱导AB-CU介导的自由基形成和氧化应激的产生。假设AB介导的毒性通过细胞外铜的增强，并且在AD患者的CSF中发现了铜的浓度和铜转运蛋白Ceruloplasmin。该提案是基于我们最近的观察结果，即免疫蛋白FKBP52是哺乳动物细胞中铜外排途径的新成分，并且使用siRNA或小分子抑制剂对FKBP52表达的下调，阻断了Atox1-Wilson病蛋白（WDP）的铜外排。铜出口路径。因此提出了基本问题。 FKBP52是否可以用作控制铜水平和AD进展的治疗靶标？该建议将检验以下假设：靶向免疫蛋白的siRNA或小分子药物将在细胞模型和淀粉样变性的小鼠APPSWE/PS1DE9模型中改善AB病理学的发展和进化。该建议旨在解决三个具体问题。 目标＃1。为了表征APP加工，AB生产和量化用免疫蛋白配体（FK506或JNJ460）或FKBP52-DOWNMODENMODENDLASID细胞中的细胞中的细胞内铜。 目标＃2。为了确定AB诱导的氧化损伤和神经毒性是否在FKBP52下调的神经元 - 培养物中得到缓解。 目标＃3。为了研究AB沉积和AB介导的突触病理是否受到FKBP52在TET-OFF系统控制下的诱导小鼠模型以及用免疫蛋白配体（FK506和JNJ460）长期处理的动物的FKBP52下调节的影响。