P-glycoprotein and Alzheimer's Disease

描述(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)中高表达。最近，P-gp被证明运输淀粉样蛋白-2，这是一种积聚在阿尔茨海默病(AD)患者脑细胞外液中的蛋白质。在散发性、非家族性阿尔茨海默病中，淀粉样蛋白-2由于其清除减少而不是由于其产生增加而在大脑中积聚。因此，我们假设，介导淀粉样蛋白-2清除的P-gp的活性在AD患者的血脑屏障中受到损害。我们将使用实验室最近开发的无创正电子发射断层扫描(PET)技术，通过测量轻中度AD患者和年龄匹配的认知正常志愿者血脑屏障中P-gp的活性来验证这一假设。P-gp在清除大脑中的淀粉样蛋白-2方面的重要性为治疗AD创造了一个令人兴奋的治疗机会。P-gp是一种可诱导的转运蛋白，几种公认的药物(如利福平)可以诱导P-gp的活性。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)血脑屏障中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非侵入性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中P-gp的活性。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AD患者的P-gp活性是否受到影响。这些拟议的研究有可能导致将P-gp确定为治疗AD的新的治疗靶点，AD是一种目前尚无有效治疗方法的疾病。

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.