Beta-Amyloid Clearance by Mammalian Choroid Plexus: Effect of Lead Exposure

描述（由申请人提供）：在阿尔茨海默病（AD）的病因学中，β -淀粉样蛋白（A2）在脑胞外液中的积累是淀粉样蛋白级联导致神经元细胞损伤的关键事件。我们的初步数据表明脉络膜丛从脑脊液（CSF）中分离出A2。脉络膜丛，作为构成血-脑脊液屏障的组织，根据人类和动物研究，也已知会积累有毒金属铅（Pb）。最近，我们发现急性体内铅暴露会增加该组织中A2的沉积。因此，本探索性研究计划旨在验证暴露于铅会导致脉络膜丛和脑组织中β -淀粉样蛋白积累的假设；这可能是由于铅通过影响该组织中的β -淀粉样蛋白运输和/或酶降解而改变了脉络膜丛对β -淀粉样蛋白的清除。一些独特的血脑屏障研究技术，如体外双室Transwell跨上皮模型，原位脑灌注和原位脑室-池灌注，以及过表达A2的转基因小鼠，将被用于验证研究假设。本研究将探索脑细胞外液清除A2的新途径，并确定铅暴露在这些过程中的作用。脉络膜丛中A2转运蛋白和代谢调节机制的潜在发现将有助于开发治疗和预防阿尔茨海默病的新策略。本研究将探索脑细胞外液清除A2的新途径，并确定铅暴露在这些过程中的作用。本研究的结果将提供线索，是否暴露于有毒金属铅（Pb）在一般人群可能有助于AD的病因。脉络膜丛中A2转运体和代谢调节机制的潜在发现将有助于开发治疗和预防阿尔茨海默病的新策略。

DESCRIPTION (provided by applicant): Accumulation of beta-amyloid (A2) in brain extracellular fluids is the key event in the amyloid cascade leading to neuronal cell damage in the etiology of Alzheimer's disease (AD). Our preliminary data suggest that the choroid plexus sequesters A2 from the cerebrospinal fluid (CSF). The choroid plexus, as the tissue constituting the blood-CSF barrier, is also known to accumulate toxic metal lead (Pb) based on both human and animal studies. More recently, we found that acute in vivo Pb exposure increases A2 deposition in this tissue. Thus, this exploratory research proposal is designed to test the hypothesis that exposure to Pb results in an accumulation of beta-amyloids in the choroid plexus as well as in brain tissues; this may occur as a result of Pb alteration of beta-amyloid clearance by the choroid plexus by affecting beta-amyloid transport and/or enzymatic degradation in this tissue. Several techniques unique to the blood-brain barrier research such as in vitro two-chamber Transwell trans-epithelial model, in situ brain perfusion and in situ ventriculo-cisternal perfusion, along with transgenic mice that over-express A2, will be used to test the research hypothesis. The study proposed in this application will explore novel pathways of A2 clearance from brain extracellular fluids and will define the role of Pb exposure in these processes. Potential discovery of A2 transporters and metabolic regulatory mechanisms in the choroid plexus will help develop novel strategies for treatment and prevention of Alzheimer's disease. PUBLIC HEALTH RELEVANCE This study will explore novel pathways of A2 clearance from brain extracellular fluids and will define the role of Pb exposure in these processes. Results of this study will provide clues as to whether exposure to toxic metal lead (Pb) in the general population may contribute to the AD etiology. Potential discovery of A2 transporters and metabolic regulatory mechanism in the choroid plexus will help develop novel strategies for treatment and prevention of Alzheimer's disease.