P-glycoprotein and Alzheimer's Disease

P-糖蛋白和阿尔茨海默病

• 批准号: 7803582
• 负责人: JASHVANT D Unadkat
• 金额: $ 31.97万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7803582
• 关键词: ABCB1 gene; Affect; Age; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein Precursor; Animal Model; Biological Markers; Blood - brain barrier anatomy; Brain; Breeding; Central Nervous System Diseases; Cerebral Amyloid Angiopathy; Cerebrum; Clinic; Clinical; Data; Deposition; Development; Disease; Dose; Elderly; Extracellular Fluid; Extracellular Space; Functional disorder; Funding; Future; Gatekeeping; Grant; Hepatic; Human; Human Volunteers; Image; Imaging Techniques; Imaging technology; In Vitro; Intercellular Fluid; Intestines; Knock-out; Knockout Mice; Label; Laboratories; Late Onset Alzheimer Disease; Ligands; Measurement; Measures; Mediating; Mus; NIH Program Announcements; National Institute of Mental Health; Neuraxis; P-Glycoprotein; P-Glycoproteins; Paper; Patients; Pharmaceutical Preparations; Physiological; Plasma; Population; Positron-Emission Tomography; Production; Proteins; Publishing; Relative (related person); Research; Rifampin; Rodent; Seminal; Techniques; Technology; Testing; Therapeutic; Tissue Sample; Tissues; Transgenic Mice; Verapamil; Wild Type Mouse; Xenobiotics; base; brain tissue; clinically significant; drug discovery; effective therapy; familial Alzheimer disease; in vivo; inhibitor/antagonist; innovation; method development; new therapeutic target; pre-clinical; prevent; radiotracer; response; single photon emission computed tomography; therapeutic target; tool; volunteer

DESCRIPTION (provided by applicant): P-glycoprotein (P-gp), an ABC efflux transporter, is highly expressed at the blood brain barrier (BBB). Recently, P-gp has been shown to transport amyloid-2, a protein which accumulates in the brain extracellular fluid in patients with Alzheimer's disease (AD). In sporadic, nonfamilial AD, amyloid-2 accumulates in the brain due to its reduced elimination and not due to its increased production. Therefore, we have hypothesized that the activity of P-gp, which mediates amyloid-2 clearance, is compromised at the BBB in AD patients. We will test this hypothesis by measuring P-gp activity at the BBB in mild-to-moderate AD patients and age-matched cognitively normal volunteers using a noninvasive positron emission tomography (PET) technique recently developed in our laboratories. The importance of P-gp in the clearance of amyloid-2 from the brain creates an exciting therapeutic opportunity to treat AD. P-gp is an inducible transporter and several, well-established approved drugs (e.g. rifampin), can induce P-gp activity. Therefore, our aim will be: To compare P-gp activity at the BBB in Alzheimer patients and in age-matched cognitively normal volunteers (controls), using the non-invasive technology, positron emission tomography (PET). Our studies will utilize an innovative, noninvasive PET imaging technique, developed by our laboratories, to measure P-gp activity at the BBB of patients with AD and age-matched cognitively normal volunteers. The logical progression of our studies from published data to in vivo studies in AD patients will unequivocally determine if P-gp activity is compromised in AD. These proposed studies have the potential to result in identification of P-gp as a novel therapeutic target for the treatment of AD, a disease for which no effective therapy exists.

描述（由申请人提供）：ABC外排转运蛋白P-糖蛋白（P-GP）在血脑屏障（BBB）上高度表达。最近，P-gp已显示出可转运淀粉样蛋白-2，淀粉样蛋白-2，一种在阿尔茨海默氏病（AD）患者中积聚在脑外液中的蛋白质。在零星的非家族AD中，淀粉样蛋白2由于消除的消除减少而不是由于其产量增加而积聚在大脑中。因此，我们假设介导淀粉样蛋白2清除率的P-gp的活性在AD患者的BBB中受到损害。我们将通过测量轻度至中度AD患者的BBB的P-gp活性以及使用非侵入性正常发射断层扫描（PET）技术来测量BBB的P-gp活性来检验这一假设。 P-gp从大脑清除淀粉样蛋白2中的重要性创造了令人兴奋的治疗机会来治疗AD。 P-gp是一种可诱导的转运蛋白，几种良好的认可药物（例如利福平）可以诱导P-gp活性。因此，我们的目标是：使用非侵入性技术，正电子发射断层扫描（PET）比较阿尔茨海默氏症患者和年龄匹配的认知正常志愿者（对照）的P-gp活性。我们的研究将利用由实验室开发的创新的，无创的宠物成像技术来测量AD和年龄匹配的认知正常志愿者的BBB的P-gp活性。我们的研究从公开数据到AD患者的体内研究的逻辑进展将明确确定P-gp活性是否在AD中受到损害。这些提出的研究有可能导致识别P-gp是一种用于治疗AD的新型治疗靶标，AD是不存在有效治疗的一种疾病。

项目成果

Activity of P-Glycoprotein, a β-Amyloid Transporter at the Blood-Brain Barrier, Is Compromised in Patients with Mild Alzheimer Disease.

• DOI: 10.2967/jnumed.113.130161
• 发表时间: 2014-07
• 期刊: Journal of nuclear medicine : official publication, Society of Nuclear Medicine
• 作者: Deo AK;Borson S;Link JM;Domino K;Eary JF;Ke B;Richards TL;Mankoff DA;Minoshima S;O'Sullivan F;Eyal S;Hsiao P;Maravilla K;Unadkat JD
• 通讯作者: Unadkat JD