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

描述(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)在脑细胞外液中的积累是淀粉样蛋白级联反应导致神经细胞损伤的关键事件。我们的初步数据表明，脉络丛从脑脊液中隔离A2。根据人类和动物的研究，脉络丛作为构成血-脑脊液屏障的组织，也已知积累了有毒的金属铅(铅)。最近，我们发现急性体内铅暴露增加了A2在这个组织中的沉积。因此，这项探索性研究计划旨在检验一种假设，即暴露于铅会导致脉络丛和脑组织中β-淀粉样蛋白的积累；这可能是由于铅改变了脉络丛中β-淀粉样蛋白的清除，从而影响了该组织中的β-淀粉样蛋白运输和/或酶降解。血脑屏障研究特有的几种技术，如体外双腔Transwell跨上皮模型、原位脑灌流和原位脑室脑池灌流，以及过度表达A2的转基因小鼠，将被用于检验研究假设。本申请中提出的研究将探索从脑细胞外液中清除A2的新途径，并将确定铅暴露在这些过程中的作用。脉络丛中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。这项研究将探索从脑细胞外液中清除A2的新途径，并将确定铅暴露在这些过程中的作用。这项研究的结果将为普通人群暴露于有毒金属铅是否可能与AD的病因有关提供线索。脉络丛中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.