P-glycoprotein and Alzheimer's Disease

描述（由申请人提供）：p -糖蛋白（P-gp）是一种ABC外排转运蛋白，在血脑屏障（BBB）高度表达。最近，P-gp已被证明可转运淀粉样蛋白-2，这是一种在阿尔茨海默病（AD）患者的脑细胞外液中积累的蛋白质。在散发性、非家族性AD中，淀粉样蛋白-2在大脑中积累是由于其消除减少，而不是由于其产生增加。因此，我们假设介导淀粉样蛋白-2清除的P-gp的活性在AD患者的血脑屏障处受到损害。我们将通过使用我们实验室最近开发的非侵入性正电子发射断层扫描（PET）技术测量轻度至中度AD患者和年龄匹配的认知正常志愿者血脑屏障P-gp活性来验证这一假设。P-gp在清除大脑淀粉样蛋白-2中的重要性为治疗AD创造了令人兴奋的治疗机会。P-gp是一种诱导转运体，一些已被批准的药物（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），比较阿尔茨海默病患者和年龄匹配的认知正常志愿者（对照组）血脑屏障处P-gp的活性。我们的研究将利用我们实验室开发的一种创新的、无创的PET成像技术，来测量AD患者和年龄匹配的认知正常志愿者血脑屏障处的P-gp活性。我们的研究从已发表的数据到AD患者体内研究的逻辑进展将明确地确定P-gp活性是否在AD中受损。这些拟议的研究有可能导致鉴定P-gp作为治疗阿尔茨海默病的新治疗靶点，这种疾病目前尚无有效的治疗方法。

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.